Influence of Cage Effects in Directing the Outcome of C-X Bond Forming Reactions.

Radical reactions have recently experienced a resurgence in organic chemistry after many decades of being considered to be too unselective to offer a viable solution for complex synthetic problems. Radical intermediates often have a number of different reaction pathways available to them that are all associated with insubstantial reaction barriers so that reaction outcomes can be controlled by proximity and dynamics. Cage effects consist of the effect of the surrounding medium, such as the solvent or the enzyme pocket, on the movement of radical intermediates and the medium's resulting influence over reaction outcomes and selectivity. Cage effects substantially affect the outcome of all transformations in condensed phases, which feature the intermediacy of radical pairs, and a suitable choice of the cage should thus constitute a key optimization parameter for radical reactions. This Perspective provides an overview of key aspects of the cage effect that can be of importance in synthetic chemistry and highlights its role in a number of recently reported transformations that forge C-X bonds via the intermediacy of radicals.

Site-Isolated Rhodium(II) Metalloradicals Catalyze Olefin Hydrofunctionalization.

Rh(II) porphyrin complexes display pronounced metal-centered radical character and the ability to activate small molecules under mild conditions, but catalysis with Rh(II) porphyrins is extremely rare. In addition to facile dimerization, Rh(II) porphyrins readily engage in kinetically and thermodynamically facile reactions involving two Rh(II) centers to generate stable Rh(III)-X intermediates that obstruct turnover in thermal catalysis. Here we report site isolation of Rh(II) metalloradicals in a MOF host, which not only protects Rh(II) metalloradicals against dimerization, but also allows them to participate in thermal catalysis. Access to PCN-224 or PCN-222 in which the porphyrin linkers are fully metalated by Rh(II) in the absence of any accompanying Rh(0) nanoparticles was achieved via the first direct MOF synthesis with a linker containing a transition-metal alkyl moiety, followed by Rh(III)-C bond photolysis.

Deoxyfluorination of phenols for chemoselective 18F-labeling of peptides.

The challenge of forming C-18F bonds is often a bottleneck in the development of new 18F-labeled tracer molecules for noninvasive functional imaging studies using positron emission tomography (PET). Nucleophilic aromatic substitution is the most widely employed reaction to functionalize aromatic substrates with the radioactive fluorine-18 but its scope is restricted to arenes containing electron-withdrawing substituents. Furthermore, many protic functional groups are incompatible with basic fluoride anions. Peptide substrates, which are highly desirable targets for PET molecular imaging, are particularly challenging to label with fluorine-18 because they are densely functionalized and sensitive to high temperatures and basic conditions. To expand the utility of nucleophilic aromatic substitution with fluorine-18, we describe two complementary procedures for the radiodeoxyfluorination of bench-stable and easy-to-access phenols that ensure rapid access to densely functionalized electron-rich and electron-poor 18F-aryl fluorides. The first procedure details the synthesis of an 18F-synthon and its subsequent ligation to the cysteine residue of Arg-Gly-Asp-Cys in 10.5 h from commercially available starting materials (189-min radiosynthesis). The second procedure describes the incorporation of commercially available CpRu(Fmoc-tyrosine)OTf into a fully protected peptide Lys-Met-Glu-(CpRu-Tyr)-Leu via solid-phase peptide synthesis and subsequent ruthenium-mediated uronium deoxyfluorination with fluorine-18 followed by deprotection, accomplished within 7 d (116-min radiosynthesis). Both radiolabeling methods are highly chemoselective and have conveniently been automated using commercially available radiosynthesis equipment so that the procedures described can be employed for the synthesis of peptide-based PET probes for in vivo imaging studies according to as low as reasonably achievable (ALARA) principles.

Stereochemistry in All Its Shapes and Forms: The 56th Bürgenstock Conference.

Acknowledging the crucial role of stereochemistry in fields as diverse as total synthesis, synthetic methodology, spectroscopy, and the study of the origin of life, the 56th SCS Conference on Stereochemistry, better known as the BÃ1/4rgenstock Conference, brought together a diverse range of chemistry expertise in Brunnen, Switzerland.

Sterically Controlled Late-Stage Functionalization of Bulky Phosphines.

The fine-tuning of metal-phosphine-catalyzed reactions relies largely on accessing ever more precisely tuned phosphine ligands by de-novo synthesis. Late-stage C-H functionalization and diversification of commercial phosphines offers rapid access to entire libraries of derivatives based on privileged scaffolds. But existing routes, relying on phosphorus-directed transformations, only yield functionalization of C sp 2 -H bonds in a specific position relative to phosphorus. In contrast to phosphorus-directed strategies, herein we disclose an orthogonal functionalization strategy capable of introducing a range of substituents into previously inaccessible positions on arylphosphines. The strongly coordinating phosphine group acts solely as a bystander in the sterically controlled borylation of bulky phosphines, and the resulting borylated phosphines serve as the supporting ligands for palladium during diversification through phosphine self-assisted Suzuki-Miyaura reactions.

Structural Evolution of MOF-Derived RuCo, A General Catalyst for the Guerbet Reaction.

Guerbet alcohols, a class of ß-branched terminal alcohols, find widespread application because of their low melting points and excellent fluidity. Because of the limitations in the activity and selectivity of existing Guerbet catalysts, Guerbet alcohols are not currently produced via the Guerbet reaction but via hydroformylation of oil-derived alkenes followed by aldol condensation. In pursuit of a one-step synthesis of Guerbet alcohols from simple linear alcohol precursors, we show that MOF-derived RuCo alloys achieve over a million turnovers in the Guerbet reaction of 1-propanol, 1-butanol, and 1-pentanol. The active catalyst is formed in situ from ruthenium-impregnated metal-organic framework MFU-1. XPS and XAS studies indicate that the precatalyst is composed of Ru precursor trapped inside the MOF pores with no change in the oxidation state or coordination environment of Ru upon MOF incorporation. The significantly higher reactivity of Ru-impregnated MOF versus a physical mixture of Ru precursor and MOF suggests that the MOF plays an important role in templating the formation of the active catalyst and/or its stabilization. XPS reveals partial reduction of both ruthenium and MOF-derived cobalt under the Guerbet reaction conditions, and TEM/EDX imaging shows that Ru is decorated on the edges of dense nanoparticles, as well as thin nanoplates of CoOx. The use of ethanol rather than higher alcohols as a substrate results in lower turnover frequencies, and RuCo recovered from ethanol upgrading lacks nanostructures with plate-like morphology and does not exhibit Ru-enrichment on the surface and edge sites. Notably, 1H and 31P NMR studies show that through use of K3PO4 as a base promoter in the RuCo-catalyzed alcohol upgrading, the formation of carboxylate salts, a common side product in the Guerbet reaction, was effectively eliminated.

Complexes of Platinum Group Metals with a Conformationally Locked Scorpionate in a Metal-Organic Framework: An Unusually Close Apical Interaction of Palladium(II).

We report synthetic strategies for installing platinum group metals (PGMs: Pd, Rh, Ir, and Pt) on a scorpionate-derived linker (TpmC*) within a metal-organic framework (MOF), both by room-temperature postsynthetic metalation and by direct solvothermal synthesis, with a wide range of metal loadings relevant for fundamental studies and catalysis. In-depth studies for the palladium adduct Pd(II)@Zr-TpmC* by density-functional-theory-assisted extended X-ray absorption fine structure spectroscopy reveals that the rigid MOF lattice enforces a close Pd(II)-Napical interaction between the bidentate palladium complex and the third uncoordinated pyrazole arm of the TpmC* ligand (Pd-Napical = 2.501 ± 0.067 Å), an interaction that is wholly avoided in molecular palladium scorpionates.

Metal-Organic Framework-Derived Guerbet Catalyst Effectively Differentiates between Ethanol and Butanol.

RuNi nanoparticles supported on a metal-organic framework (RuNi@MOF) and formed in situ from a ruthenium complex enclosed inside a nickel-based MOF act as a highly active catalyst for the Guerbet reaction of ethanol to 1-butanol, providing turnover numbers up to 725 000 Ru-1. Negligible activity of the RuNi@MOF ethanol upgrading catalyst system toward chemically similar 1-butanol makes it possible to synthesize the competent Guerbet substrate 1-butanol with >99% selectivity.

Facile C-F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent.

Late-stage fluorination reactions aim to reduce the synthetic limitations of conventional organofluorine chemistry with respect to substrate scope and functional group tolerance. C-F bond formation is commonly thermodynamically favorable but almost universally associated with high kinetic barriers. Apart from PhenoFluor chemistry, most modern aromatic fluorination methods reported to date rely on the use of transition metal catalysts, with C-F bonds often formed through reductive elimination. Reductive elimination chemistry to make C-X bonds becomes increasingly challenging when moving to higher atomic numbers in the periodic table from C-C to C-F, in part because of higher metal-X bond dissociation energies. The formation of C-C, C-N, and C-O bonds via reductive elimination has become routine in the 20th century, but it took until the 21st century to develop complexes that could afford general C-F bond formation. The availability of such complexes enabled the substrate scope of modern fluorination chemistry to exceed that of conventional fluorination. PhenoFluor chemistry departs from conventional reaction mechanisms for aromatic fluorination chemistry. Instead, we have revealed a concerted nucleophilic aromatic substitution reaction (CSNAr) for PhenoFluor that proceeds through a single neutral four-membered transition state. Conceptually, PhenoFluor chemistry is therefore distinct from conventional SNAr chemistry, which typically proceeds through a two-barrier process with Meisenheimer complexes as reaction intermediates. As a consequence, PhenoFluor chemistry has a larger substrate scope than conventional SNAr chemistry and can be performed on arenes as electron-rich as anilines. Moreover, PhenoFluor chemistry is tolerant of protic functional groups, which sets it apart from modern metal-mediated processes. Primary and secondary amines, alcohols, thiols, and phenols are often not tolerated under metal-catalyzed late-stage fluorination reactions because C-N and C-O reductive elimination can have lower activation barriers than C-F reductive elimination. The mechanism by which PhenoFluor chemistry forms C-F bonds not only rationalizes the substrate scope and functional group tolerance but also informs the side-product profile. Fluorinated isomers are not observed because the four-membered transition state necessitates ipso substitution. In addition, no reduced product, e.g., H instead of F incorporation, as is often observed with metal-mediated methods, has ever been observed with PhenoFluor. PhenoFluor chemistry can be used to deoxyfluorinate both phenols and alcohols. PhenoFluor is an expensive reagent that must be used stoichiometrically and therefore cannot replace cost-efficient methods to make simple fluorinated molecules on a large scale. However, PhenoFluor is often successful when other fluorination methods fail. The synthesis of 18F-labeled molecules for positron emission tomography (PET) is one application of modern fluorination chemistry for which material throughput is not an issue because of the small quantities of PET tracers used in imaging (typically nanomoles). The high emphasis on functional group tolerance, side-product profiles, and reliability combined with less stringent cost requirements render PhenoFluor-based deoxyfluorination with 18F promising for human PET imaging.

18F-Deoxyfluorination of Phenols via Ru π-Complexes.

The deficiency of robust and practical methods for 18F-radiofluorination is a bottleneck for positron emission tomography (PET) tracer development. Here, we report the first transition-metal-assisted 18F-deoxyfluorination of phenols. The transformation benefits from readily available phenols as starting materials, tolerance of moisture and ambient atmosphere, large substrate scope, and translatability to generate doses appropriate for PET imaging.

Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).

Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain (18)F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a 'leaving group' leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant (18)F-deoxyfluorination reaction of phenols, which can be used to synthesize (18)F-PET probes. Selective (18)F introduction, without the need for the common, but cumbersome, azeotropic drying of (18)F, can now be accomplished from phenols as starting materials, and provides access to (18)F-labelled compounds not accessible through conventional chemistry.

Alkyl Aryl Ether Bond Formation with PhenoFluor.

An alkyl aryl ether bond formation reaction between phenols and primary and secondary alcohols with PhenoFluor has been developed. The reaction features a broad substrate scope and tolerates many functional groups, and substrates that are challenging for more conventional ether bond forming processes may be coupled. A preliminary mechanistic study indicates reactivity distinct from conventional ether bond formation.

Late-stage fluorination: fancy novelty or useful tool?

Charming fluorine: This Essay examines the recent surge in late-stage fluorination reactions and outlines challenges that need to be overcome to increase the impact of modern fluorination methods on the synthesis of complex organofluorine compounds. It is outlined how an improved understanding of the bonding interactions of fluoride could lead to a new class of mild fluorinating reagents and a range of functional-group-tolerant reactions.

Selective Aromatic C-H Hydroxylation Enabled by η6-Coordination to Iridium(III).

We report an aromatic C-H hydroxylation protocol in which the arene is activated through η6-coordination to an iridium(III) complex. η6-Coordination of the arene increases its electrophilicity and allows for high positional selectivity of hydroxylation at the site of least electron density. Through investigation of intermediate η5-cyclohexadienyl adducts and arene exchange reactions, we evaluate incorporation of arene π-activation into a catalytic cycle for C-H functionalization.

Introduction of fluorine and fluorine-containing functional groups.

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

Application of palladium-mediated (18)F-fluorination to PET radiotracer development: overcoming hurdles to translation.

New chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging-an important milestone on the path to human PET imaging. The method, which transforms [(18)F]fluoride into an electrophilic fluorination reagent, provides access to aryl-(18)F bonds that would be challenging to synthesize via conventional radiochemistry methods.

A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging.

The unnatural isotope fluorine-18 ((18)F) is used as a positron emitter in molecular imaging. Currently, many potentially useful (18)F-labeled probe molecules are inaccessible for imaging because no fluorination chemistry is available to make them. The 110-minute half-life of (18)F requires rapid syntheses for which [(18)F]fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional [(18)F]fluoride chemistry has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of aromatic (18)F-labeled molecules via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomography (PET) tracers for anticipated applications in pharmaceutical development as well as preclinical and clinical PET imaging.