Supramolecular chemistry represents a way to mimic enzyme reactivity by using specially designed container molecules. We have shown that a chiral self-assembled M4L6 supramolecular tetrahedron can encapsulate a variety of cationic guests, with varying degrees of stereoselectivity. Reactive iridium guests can be encapsulated and the C-H bond activation of aldehydes occurs, with the host cavity controlling the ability of substrates to interact with the metal center based upon size and shape. In addition, the host container can act as a catalyst by itself. By restricting reaction space and preorganizing the substrates into reactive conformations, it accelerates the sigmatropic rearrangement of enammonium cations.

This book offers a comprehensive overview of different catalytic reactions applied to the activation of chemical bonds. Each of the seven chapters covers key C-X classes where carbon is combined with another element: chlorine, fluorine, nitrogen, sulfur, oxygen, hydrogen, and carbon. The first part of the book discusses homogeneous catalysis in the activation and transformation of C-Cl and C-F, highlighting their basic activation modes, cross-coupling, and intensive mechanisms. The second part of the book focuses on C-N, C-S, and C-O bonds, mentioning their catalytic pathways. Finally, C-H and C-C bonds, their activation, chemical transformations, and applicability are covered. Overall, the book presents methodologies that can be applied to the efficient synthesis of drug molecules and fine chemicals. Through their presentation, the authors show that synthetic chemistry can be done in greener ways that limit hazards and pollution.

This thesis presents detailed mechanistic studies on a series of important C-H activation reactions using combined computational methods and mass spectrometry experiments. It also provides guidance on the design and improvement of catalysts and ligands. The reactions investigated include: (i) a nitrile-containing template-assisted meta-selective C-H activation, (ii) Pd/mono-N-protected amino acid (MPAA) catalyzed meta-selective C-H activation, (iii) Pd/MPAA catalyzed asymmetric C-H activation reactions, and (iv) Cu-catalyzed sp3 C-H cross-dehydrogenative-coupling reaction. The book reports on a novel dimeric Pd-M (M = Pd or Ag) model for reaction (i), which successfully explains the meta-selectivity observed experimentally. For reaction (ii), with a combined DFT/MS method, the author successfully reveals the roles of MPAA ligands and a new C-H activation mechanism, which accounts for the improved reactivity and high meta-selectivity and opens new avenues for ligand design. She subsequently applies ion-mobility mass spectrometry to capture and separate the [Pd(MPAA)(substrate)] complex at different stages for the first time, providing support for the internal-base model for reaction (iii). Employing DFT studies, she then establishes a chirality relay model that can be widely applied to MPAA-assisted asymmetric C-H activation reactions. Lastly, for reaction (iv) the author conducts detailed computational studies on several plausible pathways for Cu/O2 and Cu/TBHP systems and finds a reliable method for calculating the single electron transfer (SET) process on the basis of benchmark studies.

Chapter 1 - A summary and overview of the application of self-assembled synthetic microenvironment catalysts is presented. The various clusters for which catalytic applications have been reported are introduced together, grouped by mechanism of self-assembly (i.e. hydrogen bond network or metal ligand coordination). The examples of catalysis are then discussed in the context of the nature of charge buildup in the transition state, with neutral reactions presented first, followed by reactions that develop anionic charge in the transition state, and finally reactions that develop cationic charge in the transition state. Chapter 2 - The tetrahedral [Ga4L6]12- supramolecular assembly developed in the Raymond group is shown to catalyze a bimolecular aza-Prins cyclization featuring an unexpected transannular 1,5-hydride transfer. This reaction pathway is promoted by the constrictive binding of the interior microenvironment of the cluster, and is kinetically inaccessible in bulk solution. A thorough investigation of the mechanism of this process is presented, including isotope labeling studies and kinetic analysis, indicating that the rate limiting step of the process is encapsulation of a transiently formed iminium ion and supports the proposed 1,5-hydride transfer pathway. This work represents a striking example of the enzyme-like ability of synthetic microenvironment catalysts to selectively modulate kinetic barriers in order to promote otherwise inaccessible selectivity. Chapter 3 - Catalysis of alkyl-alkyl reductive elimination from high valent transition metal complexes [such as gold(III) and platinum(IV)] by the [Ga4L6]12- Raymond cluster is described. Kinetic experiments delineate an enzyme-like Michaelis-Menten mechanism, with rate accelerations (kcat/kuncat) up to 1.9 × 107. Indirect evidence for the intermediacy of a coordinatively unsaturated encapsulated species is garnered from the observation of several persistent donor-arrested inclusion complexes, including a crystallographically characterized gold(III) cation. The catalysis of reductive elimination is further incorporated into a dual-catalytic cross coupling for which the presence of the supramolecular cluster is necessary in order to achieve efficient turnover, and the full catalytic cycle of this process is elucidated through a series of stoichiometric experiments. Chapter 4 - A novel supramolecular assembly of M4L4 stoichiometry is reported for which the addition of a guest effects an increase from S4- to T-symmetry. A mechanistic investigation of this guest-induced host isomerization revealed that the guest binding occurs by a mechanism similar to the conformational selection model for ligand binding in proteins. A comprehensive study of this simple system provides insight into analogous behavior in biophysics and enzymology, as well as important information to support future efforts in the design of more efficient self-assembled microenvironment catalysts.

Once considered the 'holy grail' of organometallic chemistry, synthetically useful reactions employing C-H bond activation have increasingly been developed and applied to natural product and drug synthesis over the past decade. The ubiquity and relative low cost of hydrocarbons makes C-H bond functionalization an attractive alternative to classical C-C bond forming reactions such as cross-coupling, which require organohalides and organometallic reagents. In addition to providing an atom economical alternative to standard cross - coupling strategies, C-H bond functionalization also reduces the production of toxic by-products, thereby contributing to the growing field of reactions with decreased environmental impact. In the area of C-C bond forming reactions that proceed via a C-H activation mechanism, rhodium catalysts stand out for their functional group tolerance and wide range of synthetic utility. Over the course of the last decade, many Rh-catalyzed methods for heteroatom-directed C-H bond functionalization have been reported and will be the focus of this review. Material appearing in the literature prior to 2001 has been reviewed previously and will only be introduced as background when necessary. The synthesis of complex molecules from relatively simple precursors has long been a goal for many organic chemists. The ability to selectively functionalize a molecule with minimal pre-activation can streamline syntheses and expand the opportunities to explore the utility of complex molecules in areas ranging from the pharmaceutical industry to materials science. Indeed, the issue of selectivity is paramount in the development of all C-H bond functionalization methods. Several groups have developed elegant approaches towards achieving selectivity in molecules that possess many sterically and electronically similar C-H bonds. Many of these approaches are discussed in detail in the accompanying articles in this special issue of Chemical Reviews. One approach that has seen widespread success involves the use of a proximal heteroatom that serves as a directing group for the selective functionalization of a specific C-H bond. In a survey of examples of heteroatom-directed Rh catalysis, two mechanistically distinct reaction pathways are revealed. In one case, the heteroatom acts as a chelator to bind the Rh catalyst, facilitating reactivity at a proximal site. In this case, the formation of a five-membered metallacycle provides a favorable driving force in inducing reactivity at the desired location. In the other case, the heteroatom initially coordinates the Rh catalyst and then acts to stabilize the formation of a metal-carbon bond at a proximal site. A true test of the utility of a synthetic method is in its application to the synthesis of natural products or complex molecules. Several groups have demonstrated the applicability of C-H bond functionalization reactions towards complex molecule synthesis. Target-oriented synthesis provides a platform to test the effectiveness of a method in unique chemical and steric environments. In this respect, Rh-catalyzed methods for C-H bond functionalization stand out, with several syntheses being described in the literature that utilize C-H bond functionalization in a key step. These syntheses are highlighted following the discussion of the method they employ.