The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.

The Halogen Bond

Catalytic transformation of ubiquitous C–H bonds into valuable C–N bonds offers an efficient synthetic approach to construct N-functionalized molecules. Over the last few decades, transition metal catalysis has been repeatedly proven to be a powerful tool for the direct conversion of cheap hydrocarbons to synthetically versatile amino-containing compounds. This Review comprehensively highlights recent advances in intra- and intermolecular C–H amination reactions utilizing late transition metal-based catalysts. Initial discovery, mechanistic study, and additional applications were categorized on the basis of the mechanistic scaffolds and types of reactions. Reactivity and selectivity of novel systems are discussed in three sections, with each being defined by a proposed working mode.

Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications

We introduce density functional theory and review recent progress in its application to transition metal chemistry. Topics covered include local, meta, hybrid, hybrid meta, and range-separated functionals, band theory, software, validation tests, and applications to spin states, magnetic exchange coupling, spectra, structure, reactivity, and catalysis, including molecules, clusters, nanoparticles, surfaces, and solids.

Density functional theory for transition metals and transition metal chemistry

Based on its generally accessible I/II redox couple and bioavailability, copper plays a wide variety of roles in nature that mostly involve electron transfer (ET), O2 binding, activation and reduction, NO2− and N2O reduction and substrate activation. Copper sites that perform ET are the mononuclear blue Cu site that has a highly covalent CuII-S(Cys) bond and the binuclear CuA site that has a Cu2S(Cys)2 core with a Cu-Cu bond that keeps the site delocalized (Cu(1.5)2) in its oxidized state. In contrast to inorganic Cu complexes, these metalloprotein sites transfer electrons rapidly often over long distances, as has been previously reviewed.1–4 Blue Cu and CuA sites will only be considered here in their relation to intramolecular ET in multi-center enzymes. The focus of this review is on the Cu enzymes (Figure 1). Many are involved in O2 activation and reduction, which has mostly been thought to involve at least two electrons to overcome spin forbiddenness and the low potential of the one electron reduction to superoxide (Figure 2).5,6 Since the Cu(III) redox state has not been observed in biology, this requires either more than one Cu center or one copper and an additional redox active organic cofactor. The latter is formed in a biogenesis reaction of a residue (Tyr) that is also Cu catalyzed in the first turnover of the protein. Recently, however, there have been a number of enzymes suggested to utilize one Cu to activate O2 by 1e− reduction to form a Cu(II)-O2•− intermediate (an innersphere redox process) and it is important to understand the active site requirements to drive this reaction. The oxidases that catalyze the 4e−reduction of O2 to H2O are unique in that they effectively perform this reaction in one step indicating that the free energy barrier for the second two-electron reduction of the peroxide product of the first two-electron step is very low. In nature this requires either a trinuclear Cu cluster (in the multicopper oxidases) or a Cu/Tyr/Heme Fe cluster (in the cytochrome oxidases). The former accomplishes this with almost no overpotential maximizing its ability to oxidize substrates and its utility in biofuel cells, while the latter class of enzymes uses the excess energy to pump protons for ATP synthesis. In bacterial denitrification, a mononuclear Cu center catalyzes the 1e- reduction of nitrite to NO while a unique µ4S2−Cu4 cluster catalyzes the reduction of N2O to N2 and H2O, a 2e− process yet requiring 4Cu’s. Finally there are now several classes of enzymes that utilize an oxidized Cu(II) center to activate a covalently bound substrate to react with O2.



Figure 1

Copper active sites in biology.





Figure 2

Latimer Diagram for Oxygen Reduction at pH = 7.0 Adapted from References 5 and 6.



This review presents in depth discussions of all these classes of Cu enzymes and the correlations within and among these classes. For each class we review our present understanding of the enzymology, kinetics, geometric structures, electronic structures and the reaction mechanisms these have elucidated. While the emphasis here is on the enzymology, model studies have significantly contributed to our understanding of O2 activation by a number of Cu enzymes and are included in appropriate subsections of this review. In general we will consider how the covalency of a Cu(II)–substrate bond can activate the substrate for its spin forbidden reaction with O2, how in binuclear Cu enzymes the exchange coupling between Cu’s overcomes the spin forbiddenness of O2 binding and controls electron transfer to O2 to direct catalysis either to perform two e− electrophilic aromatic substitution or 1e− H-atom abstraction, the type of oxygen intermediate that is required for H-atom abstraction from the strong C-H bond of methane (104 kcal/mol) and how the trinuclear Cu cluster and the Cu/Tyr/Heme Fe cluster achieve their very low barriers for the reductive cleavage of the O-O bond.

Much of the insight available into these mechanisms in Cu biochemistry has come from the application of a wide range of spectroscopies and the correlation of spectroscopic results to electronic structure calculations. Thus we start with a tutorial on the different spectroscopic methods utilized to study mononuclear and multinuclear Cu enzymes and their correlations to different levels of electronic structure calculations.

/pdf/copper-active-sites-in-biology-lhhabv47if.pdf

Copper Active Sites in Biology

https://www.pnas.org/content/pnas/90/5/1635.full.pdf

Supramolecular chemistry.

Halogen bonding is a noncovalent interaction similar to hydrogen bonding, which is based on electrophilic halogen substituents. Hydrogen-bonding-based organocatalysis is a well-established strategy which has found numerous applications in recent years. In light of this, halogen bonding has recently been introduced as a key interaction for the design of activators or organocatalysts that is complementary to hydrogen bonding. This Concept features a discussion on the history and electronic origin of halogen bonding, summarizes all relevant examples of its application in organocatalysis, and provides an overview on the use of cationic or polyfluorinated halogen-bond donors in halide abstraction reactions or in the activation of neutral organic substrates.

Halogen Bonding in Organic Synthesis and Organocatalysis.

In the last few decades, "unusual" noncovalent interactions like anion-π and halogen bonding have emerged as interesting alternatives to the ubiquitous hydrogen bonding in many research areas This is also true, to a somewhat lesser extent, for chalcogen bonding, the noncovalent interaction involving Lewis acidic chalcogen centers Herein, we aim to provide an overview on the use of chalcogen bonding in crystal engineering and in solution, with a focus on the recent developments concerning intermolecular chalcogen bonding in solution-phase applications In the solid phase, chalcogen bonding has been used for the construction of nano-sized structures and the self-assembly of sophisticated self-complementary arrays In solution, until very recently applications mostly focused on intramolecular interactions which stabilized the conformation of intermediates or reagents In the last few years, intermolecular chalcogen bonding has increasingly also been exploited in solution, most notably in anion recognition and transport as well as in organic synthesis and organocatalysis

Chalcogen Bonding: An Overview

Over the last 15 years, hydrogen-bond donors, such as thiourea derivatives, have been used as noncovalent organocatalysts with ever-increasing sophistication. Yet, despite the large structural variety of the currently known noncovalent organocatalysts, virtually all are based on the same interacting atom: positively polarized hydrogen. Although it has been known for a long time that compounds featuring electrophilic halogen substituents also form adducts with Lewis bases, the corresponding interaction (“halogen bonding”) 4] was mostly ignored until the 1990s. An important difference between these two noncovalent interactions is the invariably high directionality of halogen bonds, with R X LB angles that are close to 1808 (X = Cl,Br,I; LB = Lewis base). Most studies involving halogen bonds are related to the solid state and to crystal engineering, but in recent years an increasing number of applications in solution-phase have been published, including fundamental studies and reports on anion receptors. In organocatalysis, the involvement of halogen bonds has only been postulated in two cases. Bolm et al. reported that iodoperfluoroalkanes catalyze the reduction of quinoline derivatives. The participation of halogen bonds in this reaction was derived from experimental observations. In a second example, iodine trichloride was reported to catalyze the ring-opening polymerization of l-lactide. The elucidation of the exact mode of action of this highly reactive interhalogen compound is not trivial, though, and in both reported cases the analysis is further complicated by the possible presence of traces of acid. One particular application of hydrogen-bonding organocatalysts is based on the coordination to anions and/or the abstraction of the latter from organic substrates (“anion binding mechanism”). Recently, we could show that halogen-bond donors may also serve as activators in a halide-abstraction benchmark reaction. To date, however, only dicationic compounds (based on either imidazolium, pyridinium, or 1,2,3-triazolium backbones) proved to be active, and stoichiometric amounts of the halogen-bond donor needed to be employed. As the use of cationic compounds comes along with several limitations (for example, concerning solubility, synthetic accessibility, and the presence of counteranions), our next goal was to design neutral halogen-bond donors for use as activators or, ideally, organocatalysts. At present, our studies have primarily proof-of-principle character to demonstrate the feasibility of halogen-bondbased organocatalysis. In the long term, we envision that halogen-based organocatalysts and hydrogen-bond donors will complement each other. Halogen-bond donors might be especially suitable for Lewis basic substrates featuring heavier elements (such as sulfur, phosphorous, or the halogens) or for certain reaction conditions. Furthermore, neutral fluorinated halogen-bond donors will likely allow the use of very nonpolar or fluorinated solvents in organocatalysis. Finally, the high directionality of halogen bonds might prove advantageous in future halogen-bond-catalyzed enantioselective transformations. In analogy to thiourea organocatalyst 1, we strove to develop multidentate halogen-based Lewis acids without further functional groups to study the isolated effect of halogen bonding. The 2,6-diiodo-3,4,5-trifluorophenyl group (Scheme 1) was chosen as building block for several reasons,

Organocatalysis by Neutral Multidentate Halogen-Bond Donors†

Halogen‐Bond‐Induced Activation of a Carbon–Heteroatom Bond

Halogen bonding, the noncovalent interaction based on electrophilic halogen substituents, features very interesting properties, as illustrated by numerous applications continuously emerging in rece...

Stefan M. Huber

Papers

Halogen Bonding in Organic Synthesis and Organocatalysis.

Chalcogen Bonding: An Overview

Organocatalysis by Neutral Multidentate Halogen-Bond Donors†

Halogen‐Bond‐Induced Activation of a Carbon–Heteroatom Bond

Catalysis of Organic Reactions through Halogen Bonding