Formation Of Carbon-halogen Bonds Research Articles

C-H Bond Functionalization of N-Heteroarenes Mediated by Selectfluor.

Herein, recent developments for Selectfluor-mediated C-H functionalization of N-heteroarenes are described. This type of C-H bond activation is an attractive and competitive alternative to traditional methodologies, allowing the functionalization of a variety of chemical functions. In addition, Selectfluor is a more sustainable and economically accessible oxidant compared with expensive/toxic metals or hazardous peroxides. For a practical understanding, the current review classified systematically the reported strategies in four subsections as follows: (1) carbon-carbon formation, (2) carbon-nitrogen bond formation, (3) carbon-chalcogen bond, and (4) carbon-halogen bond formation. Mechanistic aspects and reaction conditions are fully discussed to provide an understanding of the aspects that govern C-H functionalization in N-heteroarenes mediated by Selectfluor.

Closing the Cycle as It Begins: Synthesis of ortho-Iodobiaryls via Catellani Reaction.

Despite the advances in the field of carbon-halogen bond formation, the straightforward catalytic access to selectively functionalized iodoaryls remains a challenge. Here, we report a one-pot synthesis of ortho-iodobiaryls from aryl iodides and bromides by palladium/norbornene catalysis. This new example of Catellani reaction features the initial cleavage of a C(sp2 )-I bond, followed by the key formation of a palladacycle through ortho C-H activation, the oxidative addition of an aryl bromide and the ultimate restoration of the C(sp2 )-I bond. A large variety of valuable o-iodobiaryls has been synthesized in satisfactory to good yields and their derivatization have been described too. Beyond the synthetic utility of this transformation, a DFT study provides insights on the mechanism of the key reductive elimination step, which is driven by an original transmetallation between palladium(II)-halides complexes.

(2‐Pyridyl)sulfonyl Groups for ortho‐Directing Palladium‐ Catalyzed Carbon–Halogen Bond Formation at Functionalized Arenes

AbstractWe describe an efficient palladium‐catalyzed selective C–H ortho‐monohalogenation (X=I, Br, Cl, F) of various functionalized (2‐pyridyl)arylsulfones. ortho‐, meta‐ and para‐functionalization is tolerated at the arene group which undergoes C–H halogenation. Some modifications are also possible on the 2‐(arylsulfonyl)heteroaryl directing groups. A comparison of the halogenation efficiency suggests that bromination is the practical method of choice, while chlorination and fluorination are possible but more challenging. Under forcing conditions ortho‐dihalogenation can also be achieved.magnified image

Manganese Catalyzed C-H Halogenation.

The remarkable aliphatic C-H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates. In this Account, we discuss recently developed carbon-halogen bond formation, including fluorination reactions catalyzed by manganese porphyrins and related salen species. We found that biphasic sodium hypochlorite/manganese porphyrin systems can efficiently and selectively convert even unactivated aliphatic C-H bonds to C-Cl bonds. An understanding of this novel reactivity derived from results obtained for the oxidation of the mechanistically diagnostic substrate and radical clock, norcarane. Significantly, the oxygen rebound rate in Mn-mediated hydroxylation is highly correlated with the nature of the trans-axial ligands bound to the manganese center (L-Mn(V)═O). Based on the ability of fluoride ion to decelerate the oxygen rebound step, we envisaged that a relatively long-lived substrate radical could be trapped by a Mn-F fluorine source, effecting carbon-fluorine bond formation. Indeed, this idea led to the discovery of the first Mn-catalyzed direct aliphatic C-H fluorination reactions utilizing simple, nucleophilic fluoride salts. Mechanistic studies and DFT calculations have revealed a trans-difluoromanganese(IV) species as the key fluorine transfer intermediate. In addition to catalyzing normal (19)F-fluorination reactions, manganese salen complexes were found to enable the incorporation of radioactive (18)F fluorine via C-H activation. This advance represented the first direct Csp(3)-H bond (18)F labeling with no-carrier-added [(18)F]fluoride and facilitated the late-stage labeling of drug molecules for PET imaging. Given the high reactivity and enzymatic-like selectively of metalloporphyrins, we envision that this new Heteroatom-Rebound Catalysis (HRC) strategy will find widespread application in the C-H functionalization arena and serve as an effective tool for forming new carbon-heteroatom bonds at otherwise inaccessible sites in target molecules.

Fertile Ground

Fertile Ground

Carbon–Halogen Bond Formation by the Reductive Elimination of PdII Species

AbstractIt is well known that Pd0 undergoes oxidative addition to organic halides, especially aryl or vinyl halides. In the contrast, the formation of organic halides by reductive elimination of RPdIIX (X=halogen) has been mostly ignored until very recently. This Focus Review discusses recent developments in palladium‐catalyzed carbon–halogen bond formation by the reductive elimination of RPdIIX. These new developments have enriched the scope of palladium‐catalyzed reactions, and provide a new way to construct carbon–halogen bonds.

Orthometallation as a Strategy in Pd-mediated Organic Synthesis

The orthopalladated complexes are among the most representative Pd(II) compounds. They display a wide prospect of applications, but they are mainly known by their use as intermediates in metal-mediated organic synthesis. In this review we describe how palladacycles are used to build up new molecules through regioselective formation of C-halogen, C-O, C-N, C-P, C-S and C-C bonds, either under catalytic or stoichiometric conditions. This methodology is based on the selective incorporation of the Pd into the organic skeleton to be modified and subsequent reactivity of the Pd-C bond toward different substrates. In many cases this strategy is alternative or even competitive, improving standard organic methods. The most recent achievements of the last five years will be covered here, presenting only the most impressive results. Keywords: CH activation, orthopalladation, palladium, insertion, oxidative coupling, CARBON-HALOGEN BOND FORMATION, CARBON-OXYGEN BOND FORMATION, CARBON-NITROGEN BOND FORMATION, ARYLATIONS, dibenzofurans, methyloximes, heteroarenes, norbornene, organometallic reagent, disulfide intermediate

Integrating carbon–halogen bond formation into medicinal plant metabolism

Halogenation, once considered a rare occurrence in nature, has now been observed in many natural product biosynthetic pathways1. However, only a small fraction of halogenated compounds have been isolated from terrestrial plants2. Given the impact that halogenation can have on the biological activity of natural products1, we rationalized that introduction of halides into medicinal plant metabolism would provide the opportunity to rationally bioengineer a broad variety of novel plant products with altered, and perhaps improved, pharmacological properties. Here we report that chlorination biosynthetic machinery from soil bacteria can be successfully introduced into the medicinal plant Catharanthus roseus (Madagascar periwinkle). These prokaryotic halogenases function within the context of the plant cell to generate chlorinated tryptophan, which is then shuttled into monoterpene indole alkaloid metabolism to yield chlorinated alkaloids. A new functional group– a halide– is thereby introduced into the complex metabolism of C. roseus, and is incorporated in a predictable and regioselective manner onto the plant alkaloid products. Medicinal plants, despite their genetic and developmental complexity, therefore appear to be a viable platform for synthetic biology efforts.

ChemInform Abstract: Reaction of Phenylchlorocarbene and Diphenylcarbene with the Carbon- Chlorine Bond: Kinetics and Mechanisms

The reactions of phenylchlorocarbene (PCC) and diphenylcarbene (DPC) with carbon-chlorine bonds were investigated by laser flash photolysis techniques, product studies, and electrochemical methods. The data with both carbenes are consistent with a polar chlorine atom transfer to form radical pairs. The PCC reaction can be thought of as an inner sphere electron transfer from the carbene to the carbon-halogen bond in which there is partial carbon-halogen bond formation in the transition state. The transition state is thought to involve a crossing between closed- and open-shell singlet surfaces. The data obtained in the reaction of DPC with chlorine donors resembles the data obtained with PCC but is more difficult to interpret because the multiplicity of the state reacting with the C-Cl bond is unclear. 40 refs., 10 figs., 9 tabs.

Finite-temperature effects in enzymatic reactions — Insights from QM/MM free-energy simulations

We report potential-energy and free-energy data for three enzymatic reactions: carbon–halogen bond formation in fluorinase, hydrogen abstraction from camphor in cytochrome P450cam, and chorismate-to-prephenate Claisen rearrangement in chorismate mutase. The results were obtained by combined quantum mechanics/molecular mechanics (QM/MM) optimizations and two types of QM/MM free-energy simulations (free-energy perturbation and umbrella sampling) using semi-empirical or density-functional QM methods. Based on these results and our previously published free-energy data on electrophilic substitution in para-hydroxybenzoate hydroxylase, we discuss the importance of finite-temperature effects in the chemical step of enzyme reactions. We find that the entropic contribution to the activation barrier is generally rather small, usually of the order of 5 kJ mol–1 or less, consistent with the notion that enzymes bind and pre-organize the reactants in the active site. A somewhat larger entropic contribution is encountered in the case of chorismate mutase where the pericyclic transition state is intrinsically more rigid than the chorismate reactant (also in the enzyme). The present results suggest that barriers from QM/MM geometry optimization may often be close to free-energy barriers for the chemical step in enzymatic reactions.

Organocatalyzed direct asymmetric α-halogenation of carbonyl compounds

The formation of carbon-halogen bonds in an enantioselective manner is an important reaction because it leads to optically active halogen compounds, which are useful intermediates for further elaboration to other valuable compounds. Within the past few years various enantioselective alpha-halogenations of carbonyl compounds by asymmetric organocatalysis have been reported. Most importantly, these recent developments have greatly enhanced the synthetic utility of alpha-halogenations and opened up a promising new frontier in organic synthesis.

Metal‐Mediated Formation of Carbon–Halogen Bonds

Organic halides represent basic starting materials for numerous metal-catalyzed organic transformations. Generally, the carbon-halogen is broken in the first step, that is, an oxidative addition reaction, of the catalytic cycle. On the other hand, very little is known about the reverse reaction, carbon-halogen reductive elimination from a transition-metal center. In this Concept article, we describe the examples of C(sp(3))-halide and C(sp(2))-halide reductive-elimination reactions which demonstrate that this type of reactivity can be quite common in organometallic chemistry. Although the thermodynamic driving force for the formation of carbon-halogen bonds is relatively small, the kinetic barrier for these reactions can also be low. Thus, C-halide reductive elimination can compete favorably with the more established organic transformations, such as C-C reductive elimination.

The structure of flavin‐dependent tryptophan 7‐halogenase RebH

Enzyme catalyzed regio- and stereo-specific halogenations influence the biological activity of a diverse array of therapeutically important natural products, including the antibiotics vancomycin and chloramphenicol as well as the anticancer agents calicheamicin and rebeccamycin. The major class of enzymes responsible for this challenging synthetic reaction, the flavin-dependent halogenases, catalyzes the formation of carbon-halogen bonds using flavin, a halide ion (Cl{sup -}, Br{sup -} or I{sup -}), and O{sub 2}. Recent mechanistic and structural advances achieved with the model flavin-dependent tryptophan 7-halogenases PrnA and RebH have greatly enhanced the level of understanding of this unique reaction. According to these studies, the mechanism for tryptophan halogenation proceeds via FAD(C4a)-OOH activation of a chloride ion into the transient chlorinating species HOCl. The key evidence for the requirement of a transient chlorinating species is the discovery that a {approx}10-{angstrom}-long tunnel separates FAD and tryptophan in the ligand-bound form of PrnA. In a recent compelling study to elucidate the strategy by which RebH controls this highly reactive and indiscriminant oxidant, a Lys79-{var_epsilon}NH-Cl chloramine intermediate was implicated as the actual chlorinating species within RebH and a structural investigation of RebH was reported. Here we report our independent structural analysis of Lechevalieria aerocolonigenes RebH (Uni-Prot accession numbermore » Q8KHZ8, 530 amino acids) in its apo-form as well as in a complex with both tryptophan and FAD.« less

New frontiers in biological halogenation.

The synthesis of halogenated compounds in biological systems is well established, yet the mechanisms by which these compounds are formed are poorly understood. Many commercially important compounds, such as pharmaceuticals and agrochemicals, contain halogens; indeed some halogenated natural products, such as the antibiotic vancomycin, are themselves valuable. Furthermore, several environmentally significant organohalogens can be formed naturally, for example it is likely that a significant proportion of the atmospheric bromomethane is produced by higher plants (Gan et al. 1998). While chemical synthesis of organohalogens can be difficult, the biological production of these compounds occurs under relatively mild conditions and often with a greater degree of specificity. Therefore an understanding of the biosynthesis of halometabolites, and in particular, the enzymology of carbon-halogen bond formation, may provide convenient biotechnological methods for the halogenation of organic compounds. For over 30 years haloperoxidases were the only halogenating enzymes that had been identified and it was largely accepted that these enzymes were responsible for almost all biological halogenation reactions. However, in recent years evidence has accumulated pointing to the existence of other halogenases and now the nature of these enzymes is being revealed. This review concentrates on the occurrence, mechanism and biocatalytic potential of the halogenating enzymes that are currently known.

The nature of the transition state in diarylmethyl cation – nucleophile combination reactions as probed by secondary α-deuterium isotope effects

Transition-state structures for the carbocation–nucleophile combination reactions of (4-substituted-4'- methoxydiphenyl)methyl cations with water, chloride, and bromide ions in acetonitrile–water mixtures have been investigated by measuring the secondary α-deuterium kinetic and equilibrium isotope effects. Rate constants in the combination direction were measured with laser flash photolysis. Equilibrium constants were measured for the water reaction by a comparison method in moderately concentrated sulfuric acid solutions, for the bromide reaction via the observation of reversible combination, and for the chloride reaction from the ratio of the combination rate constant and the rate constant for the ionization of the diarylmethyl chloride product. The fraction of bond making in the transition state has been calculated as the ratio log (kinetic isotope effect):log (equilibrium isotope effect). For the water reaction, there is 50–65% bond making in the transition state; this is also true for cations that are many orders of magnitude less reactive. The same conclusions, 50–65% bond formation in the transition state independent of reactivity, have previously been made in correlations of log kw vs. log KR. Thus, two quite different measures of transition structure provide the same result. The kH:kD values for the halide combinations in 100% acetonitrile are within experimental error of unity. This is consistent with suggestions that these reactions are occurring with diffusional encounter as the rate-limiting step. Addition of water has a dramatic retarding effect on the halide reactions, with rate constants decreasing steadily with increased water content. Small inverse kinetic isotope effects are observed (in 20% acetonitrile:80% water) indicating that carbon—halogen bond formation is rate-limiting. Comparison of the kinetic and equilibrium isotope effects shows ~25 and ~40% bond formation in the transition states for the reactions with bromide and chloride, respectively.Key words: carbocation, isotope effect, transition state, halide.

Biosynthesis of halogenated metabolites by bacteria.

Halogenated metabolites, originally thought to be infrequent in nature, are actually nothing unusual at all, and are produced by many different organisms, including bacteria. Whereas marine bacteria usually produce brominated compounds, terrestrial bacteria preferentially synthesize chlorometabolites, but fluoro- and iodometabolites can also be found. Haloperoxidases, enzymes capable of catalyzing the formation of carbon halogen bonds in the presence of hydrogen peroxide and halide ions (Cl-, Br- and I-) have been isolated and characterized from different bacteria. These enzymes turned out to be very unspecific and are obviously not the type of halogenating enzymes responsible for the formation of halometabolites in bacteria. A yet-unknown type of halogenating enzyme having both substrate and regio-specificity must be involved in the biosynthesis of halogenated compounds.

The functionalization of saturated hydrocarbons. Part 25. Ionic substitution reactions in GoAgg IV chemistry: the formation of carbon-halogen bonds

GoAgg IV chemistry (Fe (III) species, tert-butyl hydroperoxide in a mixture of pyridine and acetic acid) in the presence of LiCl can transform saturated hydrocarbons efficiently into the corresponding alkyl chlorides. The transformation into monosubstituted alkyl derivatives by “ionic trapping” reagents arising from the interception of the first intermediate of the system supports the presence of a high valent VFe-C species. Mechanistic studies suggest a possible pathway operating via an Fe-centered ligand coupling. In addition, the production of alkyl chlorides and alkyl bromides could also be achieved employing this system in the presence of halogenating reagents such as CCl 4 and BrCCl 3.

Purification of bromoperoxidase from Pseudomonas aureofaciens.

A Bromoperoxidase has been isolated and purified from Pseudomonas aureofaciens ATCC 15926 mutant strain ACN. The purified enzyme was homogeneous as determined by polyacrylamide gel electrophoresis and ultracentrifugation. This bromoperoxidase can utilize bromide ions in the presence of hydrogen peroxide and a halogen acceptor for the catalytic formation of carbon-halogen bonds. The homogeneous enzyme also has peroxidase and catalase activity. Based on the results from gel filtration and ultracentrifugation, the molecular weight of this procaryotic bromoperoxidase is 155,000 to 158,000. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis shows a single band having the mobility of a 77,000-molecular-weight species. We thus conclude that this bromoperoxidase exists in solution as a dimeric species. The heme prosthetic group of bromoperoxidase is ferriprotoporphyrin IX. The spectral properties of the native and reduced enzyme are reported. This bromoperoxidase is the first halogenating enzyme purified from procaryotic sources.

Purification and properties of bromoperoxidase from Penicillus capitatus.

A bromoperoxidase has been isolated and purified from the marine green algae, Penicillus capitatus. The purified enzyme is homogenous as determined by polyacrylamide gel electrophoresis and ultracentrifugation. Bromoperoxidase can utilize bromide ions in the presence of hydrogen peroxide and a halogen acceptor for the catalytic formation of carbon-halogen bonds. Based on equilibrium ultracentrifugation results the molecular weight of bromoperoxidase is 97,600. Sodium dodecyl sulfate polyacrylamide gel electrophoresis shows a single band having the mobility of a 55,000 molecular weight species. We thus conclude that bromoperoxidase exists in solution as a dimeric species. The heme prosthetic group of bromoperoxidase is ferriprotoporphyrin IX. The spectral properties of the native and reduced enzyme and cyanide, azide, and carbonmonoxy-reduced derivatives are reported. Amino acid analyses indicate that bromoperoxidase is rich in aspartic and glutamic acid residues, while being deficient in basic amino acid residues. In terms of enzymic activity, comparative data places bromoperoxidase closer to horseradish peroxidase than to chloroperoxidase and catalase.