Personal from Raymond Dwek I first met Richard at a CIBA conference on antibodies in 1984. Our friendship blossomed from that time. I admired his work, and it was so rewarding to see the way he subsequently built Scripps. Under his inspirational leadership, it became a flagship for chemistry and biology. He had brilliant scientific taste, and this led to some extraordinary scientists joining the institute. His medical degree and flair for chemistry were a wonderful combination. His knowledge was enormously wide. He knew almost instinctively what the major scientific problems were in the fields of chemistry and immunology. His energy and enthusiasm were contagious and so often after a talk with Richard, I went to the literature to ensure I had understood all his ideas! His authority came from his science. Having been under the influence of Rodney Porter, and later Elvin Kabat, I saw Richard as a major figure in immunochemistry. He had been part of virtually every major advance in the field for 25 years and, remarkably, a pioneer in most. His discovery and contributions to the field of combinatorial antibody libraries, like those of Greg Winter, revolutionized immunochemistry. The libraries allowed construction of immunological repertoires that were many orders of magnitude larger than those which are naturally occurring. Libraries such as phage, yeast, and Escherichia coli surfaces, unlike their natural counterparts, are not restricted by the constraints of self-tolerance, which is especially important because most of the therapeutic antibodies in the clinic are antibodies to self. Without doubt, antibody libraries have profound implications for human health. It was always fun being around Richard. He had a great sense of humour and a love and passion for science that encouraged his students and colleagues to try the quick-and-dirty experiment to see if it was worth continuing. The year 2007 was the beginning of regular visits to Scripps, where I became an institute professor, and where Sandra, my wife, and I spent nearly 3 months each subsequent year. Our friendship with both Nicky and Richard Lerner was amazing and deep. We travelled extensively around the world together. At Scripps, Sandra and I renewed many other friendships with faculty members. I learned a great deal there from the outstanding faculty members. Richard's frequent visits to Oxford resulted in strong links throughout the University with Scripps. His science was recognised by Oxford University where he was awarded an honorary doctorate in 2007 (Photo 1a and 1b). He was also an awardee from the Institute of Biology (now the Royal Society of Biology) in 2009 at a special event in Oxford celebrating 200 years since the birth of Charles Darwin. Photo 1 a: 2007 Richard receives an honorary degree from Oxford University for his pioneering research on catalytic antibodies. Photo 1 b: Darwin's 200th birthday. The Sheldonian theatre, Oxford University. From left to right: Public Orator, Barry Blumberg, Gunter Blobel, Richard Dawkins, Marios Papadopoulos, Bishop of Oxford, Richard Lerner. One of Richard's legacies to Oxford was to create a joint graduate D.Phil/Ph.D programme with the Scripps Research Institute. The scholars were named Skaggs scholars after L.S. Skaggs and his wife, Aline. This was the first time in its 950-year history that Oxford University had offered a degree jointly with another institution of higher learning. The course is 5 years, scholars work at both institutions and at the end receive both a PhD and a DPhil. Today it is regarded as a flagship for Oxford's Biochemistry Department (Photo 2). Photo 2: The appreciation plaque that the Department of Biochemistry has placed by the entrance of the Department expressing its gratitude towards Richard Lerner's contribution to the Skaggs-Oxford D.Phil programme. Richard saw medicinal chemistry as an essential part of any modern Biochemistry department and also helped set up a Scripps Medicinal Laboratory in the Glycobiology Institute in Oxford. Richard was always very interested in Glycobiology, a term I coined in 1988. In particular, he liked the idea that the sugars attached to the antibodies could help diversify the Fc part of the molecule with different glycoforms having different activities (Figure 1). Figure 1Open in figure viewerPowerPoint The structure of the Fc glycans can determine which part of the immune system is to be recruited and how strongly. This figure shows crystal structures of different Fc-glycoforms and their diverse effector function. Just which Fc glycans are present will determine which part of the immune system will be recruited and how strongly. Sialylation is thought to be responsible for the anti-inflammatory activity of intravenous immunoglobulin (IVIg) administered at high doses. The pro-inflammatory activity, as seen in rheumatoid arthritis comes from activation of complement through the mannose binding protein. Afucosylated IgG has a 20–40-fold increase in affinity to FcγRIIIa. The lowered Fc fucosylation in the responses to virus infection suggests a pathological role through FcγRIIIa, and may correlate with disease severity.1, 2 Perhaps the most important finding in Glycobiology, is that viral envelope glycoproteins require the calnexin cycle to fold to their 3D-structure. When a virus invades the cell, it seems to hijack the calnexin cycle. Inhibition of that cycle, temporarily, by inhibiting host enzymes (glucosidases) could be a route to create a general broad-spectrum antiviral. Targeting host enzymes was thought to be unwise but viruses might be a specific case where it can be done because there are two routes to glycoprotein folding that involve a monoglucosylated glycoform intermediate, which exists in two conformers that are in equilibrium with each other.3-5 One of these conformers can bind to calnexin and uses the calnexin chaperone pathway. This route is more specific for viral enveloped glycoproteins.4 Inhibiting the glucosidase prevents entry to this route and correct folding of the viral envelope glycoproteins. The other conformer does not bind to calnexin and folding of glycoproteins occur by other chaperone systems. This is the general route for most glycoproteins for which removal of the glucose from the intermediate glycoform allows exit to the Golgi. If there is inhibition of glucosidases by a drug, then the glucose residues are removed by a Golgi enzyme, effectively providing a salvage pathway. This allows the protein's glycosylation to proceed normally. This glycobiology approach would create a general antiviral drug as the inhibition of the host glucosidase would preferentially inhibit the pathway for the viral envelope glycoproteins. Could the virus by hijacking a folding pathway for its envelope glycoproteins have provided an Achilles heel? If so then a broad-spectrum oral antiviral is an exciting possibility. We can all imagine Richard's speculations-but he saw more than most others. In Richard's memory, my colleague Dr Constantina Fotinou and I summarise the current thoughts on a general antiviral. This based on the work of many of our colleagues in Professor Zitzmann's laboratory, from the Glycobiology Institute in Oxford, and currently, in the new Biochemistry building which incorporates the Institute. The data discussed in this article on the iminosugar MON-DNJ suggest that the pathway to the clinic for testing of this as an orally available broad- spectrum antiviral could be very nearby.

1 Introduction The mimicry of biological host-guest behavior is the foundational motivation of supramolecular chemistry.1 Since the emergence of this field in the 1970s, the imagination and creativity of chemists has fostered the appearance of thousands of examples of molecular encapsulation by synthetic receptors of diverse shapes, sizes and typology.2 Calixarenes3 and resorcinarenes4 have enjoyed enormous popularity as starting scaffolds for molecular receptors, because the pre-organized concave shapes of these macrocycles make them ideal for building up deeper hydrophobic concavities. In 1982, Cram first coined the term cavitand to describe “synthetic organic compounds that contain enforced cavities large enough to accommodate simple molecules or ions”.5 In the context of modern supramolecular chemistry, this somewhat generic definition could be applied to a plethora of different hosts assembled by assorted methods. But since its inception, the term cavitand has been applied almost exclusively to resorcin[4]arene (R4A) derived hosts (1-2, Figure 1).6 For the sake of simplicity, we will use the term “R4A derived cavitands” throughout this review to refer to monomeric hosts obtained by expansion of R4A with aromatic units through SNAr condensation reactions of the phenolic functions. Such receptors have some distinct features, namely, a cylindrical cavity that is sealed at one end and open at the other, and a fluxional behavior that allows the host to switch from the closed conformer (vase) to an open one (kite), allowing the release of guests within.7 The original concept was further refined by Rebek with the introduction of self-folding cavitands (2), featuring adjacent secondary amide groups at the rim.8 These amides engage in a cooperative hydrogen bond network that stabilizes the vase conformer, increasing the barriers of the vase-kite transition and slowing down guest exchange in turn. The platform devised by Rebek allows functionalization of one of the cavitand's wall, giving rise to the development of interesting applications such as the isolation of reactive intermediates or the development of bioinspired and supramolecular catalysis.9 Despite all these feats, we identified some downsides of the R4A derived self-folding cavitands that limit the development of new and meaningful applications, specifically in the area of catalysis. First, the binding space of these cavitands is relatively reduced, limiting the choice of guests to small molecules and substrates of limited relevance. And second, and most important, the binding space of R4A self-folding cavitands is rather rigid, severely limiting the emergence of induced-fit and conformational selection phenomena that are central to the outstanding capabilities of biological receptors (proteins and enzymes).10 This statement may sound controversial in light of previous claims of induced fit behavior in R4A derived cavitands,11 but our own Molecular Dynamics (MD) simulation studies on this matter eloquently reveal that the flexibility of these receptors is far removed from the plasticity displayed by enzymes and proteins.12 Accordingly, we envisaged the development of a completely new family of self-folding receptors with expanded binding spaces displaying genuine induced fit behavior, which should facilitate the development of applications with a wider and more significant range of guests and substrates. This account summarizes our efforts in this direction to develop new calix[5]arene (C5A) derived self-folding cavitands, with an emphasis on the design rationale.13 Figure 1Open in figure viewerPowerPoint Evolution of the self-folding cavitand concept, from rigid cavities enforced by covalent bridging of R4A (1, 2) to the more flexible structures derived from C5A and stabilized primarily by hydrogen bonding (4a, 4c, 11).

1 Introduction There is a certain class of molecules that play a prominent role in the universe of chemical compounds because their particular symmetrical shape appeals to the aesthetic sensibilities of the human mind. These include molecules that correspond to the shape of the five Platonic solids: Icosahedron, octahedron, tetrahedron, hexahedron (cubane) and dodecahedron.1 Due to the valence restrictions on carbon, only the latter three can be synthesized as hydrocarbons. Cubane (C8H8) was first isolated in 1964,2 while the synthesis of dodecahedrane (C20H20) succeeded in 1981.3 The smallest platonic hydrocarbon tetrahedrane could be synthesized so far only as a substituted derivative C4R4 with R=t-butyl.4 Heavier atom homologues of the Platonic solids have also been the target of experimental studies. Tetrahedrane structures E4R4 with bulky substituents could be prepared for the heavier group-14 elements silicon5 and germanium,6 while the tin and lead homologues are still pending their preparation. The structures and stabilities of group-14 tetrahedranes E4R4 has been the topic of several theoretical studies.7 The first synthesis of an octasilacubane was reported in 19888 which was followed by the preparation of the first octagermacubane in 19929 and octastannacubane in 1990.10, 11 Very recently, Apeloig, Bravo-Zhivotovskii and coworkers reported about a facile synthesis of an octagermacubane where six four-coordinated germanium atoms carry bulky silyl groups whereas there are two three-coordinate Ge(0) atoms at opposing edges of the octahedron.12 Octagermacubanes Ge8R6 where R is an amido or aryl ligand have previously been synthesized and structurally characterized earlier by Schnepf et al.13 The carbon parent system C8H6 was obtained as an electronic singlet species in a low-temperature argon matrix by Michl and co-workers.14 The novel octagermacubane Ge8R6 (R=Sit-butyl2methyl) (1) bears formally a single electron on the Ge(0) atoms, which are coupled with each other, making the compound a singlet biradical. Previous calculations of the model compound Ge8(NH2)6 suggested that the electronic singlet state is 23.1 kcal/mol below the triplet state.13a The calculated singlet-triplet gap of C8H6 is 10.5 kcal/mol.14 The research about E-cubanes with various group-14 atoms E and related clusters is an area of extensive research.15 The compounds Ge8R6 exhibit a peculiar bonding situation and therefore they aroused our great interest for molecules that possess unusual bonds. Here we report about a bonding analysis of 1 using various methods besides the EDA-NOCV (Energy Decomposition Analysis with Natural Orbitals for Chemical Valence) approach,16 which has proven to give detailed information about the nature of chemical bonds where the physical mechanism of interatomic interaction is described in terms of a plausible bonding model.17

Supporting Information (Additional ESI spectra, CID spectra, and temporal evolution charts from reaction monitoring) for this article is available on the WWW.

1 Introduction The Continued Value of a “Physical Organic Chemistry Lens” in 21st Century Science I was trained as a physical organic chemist by my PhD mentor Professor John H. Bowie1 and my post-doctoral mentor, the late Charles (“Chuck”) H. DePuy.2 In thinking about how to write an accounts article of work carried out in our laboratory over the past decade, I reflected on the rich history of physical organic chemistry3 and reread a series of mini essays from the IUPAC symposium in print “Physical organic chemistry for the 21st century” published 25 years ago.4 A common theme that emerged from these articles was that physical organic chemistry had matured and that the “physical and analytical tools” (e. g. NMR, kinetic orders, stereochemical and substituent effects, isotope effects and isotopic tracers) used and developed by physical organic chemists and the “intellectual tools” pioneered by physical organic chemists (e. g. reaction mechanisms, kinetics and equilibria interpreted via theory and electronic structure concepts) were now being (or likely in the future to be) deployed by scientists in other branches of chemistry or outside of chemistry.5 One such field that was identified by several authors, which I have ventured into and is the subject of this essay, is organometallic chemistry.6, 7 The Importance of Concepts in Driving New Ideas in Organic Chemistry Breslow's IUPAC essay highlighted that: “The major output of physical organic chemistry is a theory, an idea, an explanation. This may be a guide to new methodology, or practical applications, but the idea is the centerpiece.”8 This sentiment is echoed by the motivation for Professor Helmut Schwarz's important work on transition-metal-mediated C−H bond activation in methane, which is succinctly summarised in the title of his seminal review article “Chemistry with methane: concepts rather than recipes.”9 In this essay I will review some key concepts that have underpinned our work on the development of a new class of reactions. The Value of Exploiting an Understanding of Elementary Steps to the Development of New Synthetic Methodology Arguably, one of the most important concepts in transition-metal (TM) catalysis is that of elementary steps. The lens of physical organic chemistry has played a central role in uncovering and cataloguing the various mechanistic variants of many of the key elementary steps.6, 7 Indeed, solution phase,10-12 gas-phase13 and computational studies14-25 have provided a wealth of information on elementary steps. Given this important knowledge base, it is remarkable that many advances in TM catalysis have occurred by trial-and-error, serendipitous discovery or through high-throughput screening (described by MacMillan as “accelerated serendipity”26). Indeed, Perez-Temprano has noted that “Surprisingly, one strategy that has received very limited attention, despite its potential to provoke a paradigm shift in terms of sustainability, is the rational design of chemical transformations based on knowledge-driven approaches. Mechanistic investigations are typically applied as an a posteriori tool, which focuses on understanding the reaction mechanism of successful transformations.”27 Since the success or failure of a catalytic cycle depends on the performance of the reaction intermediates involved in each elementary step, Perez-Temprano champions the study and use of key reaction intermediates as “knowledge building blocks”. If we consider the Nobel prize winning “textbook” palladium-catalysed cross-coupling reactions (eq. 1, Scheme 1a),28 the idealised catalytic cycle consists of three elementary steps: (1) oxidative addition of the organic halide to a Pd(0) precursor to form the Pd(II) organometallic intermediate;29 (2) transmetallation to form a new Pd(II) organometallic intermediate with a second organometallic bond;30 (3) reductive elimination of the two organyl moieties forges the desired C−C bond and closes the catalytic cycle to return (“recycle”) the Pd(0) precursor.31 Considerable work is still being carried out: (i) in using mechanistic approaches to optimise palladium-catalysed industrial scale manufacture of drugs;32, 33 (ii) on developing new variants of these palladium cross-coupling reactions, in which other metals or ligands are used or new elementary steps are being developed (e. g. involving metals with suitable oxidation states that can react with radicals).34 Scheme 1Open in figure viewerPowerPoint Catalytic cycles for use in organic synthesis. (a) Textbook palladium-catalysed cross coupling. (b) ExIn reaction via idealised catalytic cycle. Note that both of these catalytic cycles are idealised and do not consider the fine level details of each of the elementary steps which may involve loss or addition of a ligand, L or a solvent molecule. In an excellent review, Poli et al.35 have highlighted that many other TM mediated or catalysed reactions used in organic synthesis can also be generalised into a similar set of three stages that involve TM intermediates: (1) activation of the organic fragment by a TM complex to form an organometallic intermediate, (2) transformation of the initially formed organometallic intermediate via reaction with another organic or organometallic molecule; (3) removal of the metal from the modifed, coordinated organic moiety with possible recycling of the TM. Using this “roadmap” and guided by “knowledge building blocks”, it should be possible to develop hypothesis driven TM catalytic cycles for use in organic synthesis. This “mechanisms first” approach has been adopted by a number of researchers, as highlighted for example by Chen's essay in this journal.36 Apart from academic interest, part of the drive to develop new TM processes is the motivation “…. to develop perfect chemical reactions that proceed with 100 % yield and 100 % selectivity without forming any waste products.” as articulated by Noyori.37 As has been noted by Baudoin, transition-metal-catalysed cross-coupling methods via cycles shown in Scheme 1a “…. suffer from their lack of atom and step economy, as they require the preparation and use of a stoichiometric organometallic coupling partner.”38 This arises from the need of the transmetallation step to install an organometallic bond.30 Thus a major focus over the past 2 decades has been the development of alternatives to the transmetallation step that allow installation of an organometallic bond from other organic substrates. Two key processes have been explored to introduce an organometallic bond: C−H bond activation methods39-49 and C−X bond activation of a coordinated anion to extrude a small molecule (e. g. decarboxylation of a coordinated carboxylate50-55 or desulfination of a coordinated sulfinate56-58). Metal-mediated decarboxylation and desulfination are named reactions (the Pesci59 and Peters60, 61 reactions respectively) and have rich histories for the stoichiometric preparation of organometallics in the condensed phase.62-65 The concept of fragmentation of a coordinated ligand to unmask a metal-based reactive intermediate has been pioneered in mass spectrometry based gas-phase studies by Schwarz, Beachamp, Bowers, Armentrout and others, as detailed in a review.66 In the gas phase, the equivalent of thermal activation of a coordinated ligand is the use of collision-induced dissociation (CID), which can be employed on a wide range of mass spectrometers. Inspired by Kass’ report on the use of CID to generate para deprotonated phenyllithium and phenyl sodium via double decarboxylation of metal salts of terephthalic acid, p-C6H4(CO2H)2, generated via electrospray ionization mass spectrometry,67 in 200268 we embarked on a program to study the structure and reactivity of organometallic ions formed via extrusion reactions involving decarboxylation and desulfination. We have employed ion trap mass spectrometers, which can be regarded as “complete chemical laboratories”,69, 70 since the resultant organometallic product ions can be isolated and their reactivity (both unimolcular and bimolecular) can be studied, while their structures can be interrogated via gas-phase spectroscopic methods (UV71, 72 or IR73) on suitably modified mass spectrometers.74-77 At the same time that we were studying gas-phase decarboxylation of metal carboxylates and the subsequent reactions of the resultant organometallic ions (much of this earlier work has been reviewed70, 78), there was a renaissance of condensed phase work on metal catalysed decarboxylative coupling reactions. Some landmarks include Myers’ report on the decarboxylative Heck cross-coupling reaction (Scheme 2a)79, 80 and Goossen's decarboxylative biaryl cross-coupling reaction (Scheme 2b).81 Inspired by those and other reports, we became interested in exploring if we could translate gas-phase and solution-phase mechanistic insights into the design of new synthetic methods. It occurred to us that the isoelectronic analogy between CO2 and (hetero)cumulenes opens the door to developing a new class of reactions for organic synthesis, potentially via the idealised catalytic cycle shown in Scheme 1b. Scheme 2Open in figure viewerPowerPoint Pioneering decarboxylative coupling reactions developed for organic synthesis. (a) Heck cross-coupling reaction. (b) Biaryl cross-coupling reaction. It is instructive to compare and contrast the catalytic cycles shown in Scheme 1. Just as oxidative addition (step 1 of Scheme 1a) and reductive elimination (step 3 of Scheme 1a) are the reverse of each other, so too are extrusion (step 1 of Scheme 1b) and insertion (step 2 of Scheme 1b). The transmetallation reaction (step 2 of Scheme 1a) is a type of ligand substitution reaction as is the protodemetalation reaction82 (step 3 of Scheme 1b). In contrast to the redox changes that occur at the palladium centers in the cross-coupling cycles (Scheme 1a), the cycle shown in Scheme 1b is isohypsic since there are no changes to the oxidation state of the metal in each step.83 Starting with the simplest isoelectronic molecules CO2 and CS2, we explored whether extrusion-insertion reactions could be used in a stepwise fashion to transform a coordinated carboxylate ligand into a new dithiocarboxylate ligand.1 We first studied the ion-molecule reactions between [CH3CuCH3]−, formed via double decarboxylation of [CH3CO2CuO2CCH3]− (eqs 3 and 4), and carbon disulfide in an ion trap mass spectrometer.85 [CH3CuCH3]− reacts with CS2 to yield an adduct, [CH3CuS2CCH3]− (eq. 5, 77.5 %), as well as CH3CS2− (eq. 6, 22.5 %). CID of the adduct [CH3CuS2CCH3]− gives CH3CS2−. Subsequently we showed that the copper complex [(Bphen)Cu(O2CC6H5)]2− (Bphen=bathophenanthroline) also undergoes decarboxylation and the resultant organometallic complex, [(Bphen)Cu(C6H5)]2−, reacts with CS2 to form [(Bphen)Cu(S2CC6H5)]2−.86 These studies highlighted that sequential extrusion and insertion reactions could be used to transform coordinated ligands and spurred us onto the development of the new class of reactions coined as ExIn (Extrusion-Insertion), which are discussed in detail below.87 (3) (4) (5) (6) Interlude: Where does the ExIn Reaction Fit Into the Vast Array of Organic Reaction Types? Even the experienced organic chemist can be bewildered by the numerous named reactions. The ExIn reaction shown in Eq. 2 (Scheme 1b) belongs to a class of reactions called isodesmic reactions. Below historical aspects and recent work on new organic synthetic methodology developed around the concept of isodesmic reactions are briefly summarised. 1.4.1 Origin of the Concept of Isodesmic Reactions for Use in Estimating Thermochemical Quantities In 1970, Pople and co-workers introduced the term “isodesmic” reactions to describe bond separation reactions involving chemical changes in which there is retention of the number of bonds of a given formal type, but with a change in their relation to one another.88 They illustrated this concept by using eq. 7 and then developed the use of isodesmic reactions in order to predict thermochemistry using low levels of electronic structure theory. Although Pople and co-workers were the first to define the concept of “isodesmic” reactions, the use of isodesmic reactions to predict thermochemistry is predated by the development of the widely used Benson group additivity rules, where experimentally calculated heats of formation for individual groups of atoms are used to calculate the entire theoretical heat of formation for a molecule of interest.89-91 Underpinning the development of group additivity are disproportionation reactions and Benson used eqs 8 and 9 to illustrate how of heats of formation for individual groups of atoms can be empirically derived from known heats of formation of organic molecules. 567(7) (8) (9) Since the introduction of the concept of isodesmic reactions, theoretical chemists have widely exploited these reactions to obtain accurate thermochemical quantities using low-cost methods that can be applied to large chemical systems. Applications have been far ranging, including calculation of bond dissociation energies, energetics associated with rearrangement reactions and heats of formation of reactive intermediates such as radicals.92 1.4.2 Use of the Concept of Isodesmic Reactions in Organic Synthesis to Classify Existing Reactions and to Stimulate the Development of New Synthetic Methods It has taken some time for the mainstream organic chemistry community to realise that the concept of isodesmic reactions does not just belong to the domain of theoretical chemistry, but can be a powerful way of classifying well-known synthetic reactions and as a means of stimulating the development of new reaction methods for use in organic synthesis. Indeed, the term “isodesmic reaction” did not make it into the IUPAC glossary of terms for use in physical organic chemistry until 1994, where it was noted that the Hammett equation as applied to equilibria (e. g. eq. 10) essentially deals with isodesmic processes.93 Morandi appears to have been the first to have actively used the term “isodesmic” to classify reactions used in organic synthesis in a series of 3 reviews.94-96 There are a vast array of possible isodesmic reactions and Scheme 3 illustrates some specific examples. The Nobel prize winning olefin (alkene) metathesis reaction (Scheme 3a, eq. 11) is a widely used isodesmic reaction in both academic and industrial settings.97-100 As has been pointed out in Astruc's review, this is a stunning example of the leading role that mechanistic work can take in the development of a reaction for organic synthesis.97 A special class of isodesmic reactions involves an organic molecule (donor) donating two groups to an unsaturated (acceptor) organic molecule as shown in the cartoon in Scheme 3b, and when these reactions occur under catalytic conditions they have been termed “shuttle catalysis”.94, 96 These can be further classified into whether the reactant and product donor molecules have the same functional group or not. The former are called isofunctional isodesmic reactions (Scheme 3c) and include the well-known transfer hydrogenation (eq. 12)101 and transfer hydromagnesiation (eq. 13)102-106 reactions and the more recently reported transfer hydrocyanation (eq. 14).107, 108 Very recently Morandi has added the first hydroarylation reaction to the growing repertoire of isodesmic reactions (eq. 15).109, 110 Scheme 3Open in figure viewerPowerPoint Examples of isodesmic reactions used in organic synthesis. The latter are called non-isofunctional isodesmic reactions (Scheme 3d) and variants of transfer hydrogenation (eq. 16)111 and transfer hydromagnesiation (eq. 17) are also known.112, 113 Thus the answer to the question posed in the title of this section is that the ExIn reaction can be classified as a non-isofunctional isodesmic hydroarylation reaction.

Introduction In a beautiful experiment, accompanied by theoretical investigations, Helmut Schwarz and colleagues have identified the first thermodynamically stable diatomic trication UF3+ and measured the ionisation energy of its precursor UF2+ in an energy-resolved charge-stripping experiment to yield the trication.1 The molecular trication was found to be stable with respect to Coulomb explosion into U2+ and F+, although the ionisation energy of U2+ slightly exceeds the ionisation energy of fluorine. Strong covalent bonding in UF3+ compensates the slightly unfavourable ionisation energy balance,1, 2 so that in total a stable trication emerges. We have recently suggested that highly charged molecular ions can not only be instrumental for exploring thermodynamical stability and chemical bonding in extreme charge states, but that they might also help to shed light on matter and its fundamental interactions in general.3 This was motivated by latest progress in the field of highly-charged atomic ions,4 which possess due to compressed level structures a high sensitivity to a possible variation of the fine-structure constant.5 A hypothetical drift of fundamental constants in time or variation in space has been discussed already by Dirac6 in the 1930s and is since then studied for instance in laboratory experiments or in astronomical observations. In our previous work, we have proposed PaF3+ as a promising molecule to probe a possible permanent electric dipole moment of the molecular ion that is induced by violation of parity- and time-reversal symmetry, abbreviated as -violation.3 Due to large internal electric fields, such -violation effects are strongly enhanced in polar molecules.7 Moreover, -odd effects are short-ranged and relativistic in nature and, thus, increase steeply with the nuclear charge number 8 A high molecular charge increases these effects, as the effective nuclear charge, and with this relativistic effects increase.3 A permanent electric dipole moment (EDM) discussed in this work is to be distinguished from an electric dipole moment in the intrinsic frame of a molecule, usually just called the dipole moment of a polar molecule, as the latter averages out for randomly oriented diatomic molecules, for instance. The EDM of a non-degenerate system, in contrast, must be proportional to its total angular momentum. In a molecule, the -violating EDM can be caused by several different effects: Individual charged elementary particles such as electrons or quarks can possess an EDM, composite particles like protons, neutrons or atomic nuclei can acquire an EDM, or the various interactions between particles can be -violating. In the atomic nucleus, one manifestation of -violation is the highly exotic nuclear Schiff moment, which results from a difference in charge distribution and electric dipole moment distribution in the nucleus. This is believed to be strongly enhanced in pear-shaped protactinium nuclei.9 In particular the isotope Pa is discussed in this context.10, 11 The net EDM observable in a molecule is related to the various -violating sources of this moment by so-called molecular enhancement factors , where i distinguishes the sources like the electric dipole moment of the electron ( ), the nuclear Schiff moment ( ) and the -odd scalar-pseudoscalar nucleon-electron current ( ). This bears similarity to the relation between the conventional magnetic dipole moment of an open-shell diatomic molecule and a magnetic dipole moment of the atomic nucleus, which are linked by the molecular enhancement factor that is in this case called the hyperfine-coupling tensor. We have argued that PaF3+ has a rather simple electronic structure, isoelectronic to RaF,12-19 with one electron above closed shells, so that extracting from a molecular experiment some fundamental parameters in the sense of particle physics appears more viable in PaF3+ than in UF3+.3 The Schwarz trication UF3+, however, has the particular charme to be isoelectronic to thorium monooxide (ThO). The latter has been used experimentally to obtain one of the tightest upper bounds on -violation in the electron-sector, more precisely for the electric dipole moment of the electron (eEDM), namely 20 The electronic ground state of ThO, assigned as a state, is rather insensitive to the eEDM, but the metastable state is populated in the experiment and used as a probe for a hypothetical eEDM.20 In this state, one electron occupies an orbital with pronounced d character and one electron occupies an orbital with pronounced s character, both located at Th. The high sensitivity to an eEDM stems from the orbital of high s character, which is polarized by admixture of p , as the eEDM interaction is very short-ranged and requires electron density in the vicinity of the nucleus. Recently the ThO experiment was outperformed by an experiment with HfF+, which resembles the electronic structure of ThO and has an eEDM sensitive meta-stable state as well.21 This HfF+ experiment shall in future be improved by using the heavier ThF+, which is isoelectronic to ThO but in which the sensitive state forms the electronic ground state.22-24 With our present work, we want to explore the sensitivity of various electronic states of UF3+ as possible probes for violations of fundamental symmetries. Thereby, in particular the energetic position of the state, that is the electronic ground state in ThF+, shall be determined. Furthermore, the change of energetic position and properties of the electronic states along the isoelectronic systems ThF+, PaF2+ and UF3+ are studied. All three molecules have a similar bonding pattern (see Figure 1 for energetically highest-lying pairs of bonding molecular spin-orbitals), and thus are ideal to study the change in electronic structure and properties. In the following section, we briefly outline the theoretical background and computational approach. Subsequently, we report the results obtained for several of the electronic states of UF3+ and compare molecular orbitals and molecular enhancement factors of -violation to those of ThF+ and PaF2+. We discuss the potential of UF3+ for fundamental physics research, before we finally conclude our work. Figure 1Open in figure viewerPowerPoint Energetically highest-lying bonding orbitals in ThF+, PaF2+ and UF3+ computed on the ZORA-cGHF level. Complex two-component spinor-wavefunctions are shown with alpha-spin part left and beta-spin part right. Molecules are here and in other Figures oriented with fluorine atom on the top and actinide atoms on the bottom. The color scheme of the complex spinors is given in Figure 2. Characters of the spinors are obtained from a Mulliken population analysis with values before the semicolon corresponding to the actinide atom population. The absolute phase of each spinor is arbitrary and chosen to be equal for all shown spinors. The color of the lines indicates the states used in later discussion.

Art Olson's reflections I never knew Richard Lerner to be unambitious or shy, and from the moment I met him, his enthusiasm and excitement for science made a lasting impression. He had come up to Berkeley in 1981 to visit me at the National Resource for Computation in Chemistry. I had one of the early interactive 3D computer graphics systems and he had learned of my interests in visualizing virus structure from Ian Wilson who had recently solved the influenza hemagglutinin crystal structure.1 Ian and I had both worked as crystallography postdocs at the same time in the Wiley/Harrison Labs at Harvard: Ian with Don Wiley and I with Steve Harrison, where I had worked on the first atomic structure of an intact spherical viral capsid.2, 3 Richard was anxious to map the locations of the antigenic hemagglutinin peptides that he had produced, and with Ian's structure and my 3D graphics we sat down and visualized all of them in a matter of an hour or so, clearly showing the relationship of spatial location to antigenicity. Richard was enthralled and our first papers together followed shortly4, 5. I believe that experience helped to bolster Richard's determination to start a structural biology effort at Scripps. In fact, on the spot, Richard asked me if I'd consider leaving Berkeley and coming to Scripps. Having gotten my PhD at Berkeley, and happy to have returned there after my postdoc to a permanent position as a Staff Scientist, as a “Berkeley type” I was somewhat resistant to move to Southern California. Since my office was up on the hill at Lawrence Berkeley Labs, and I had a spectacular view of the San Francisco Bay and the Golden Gate Bridge, I defensively asked him if he could match such a view. Without skipping a beat – he said that he could and invited me to visit. During the visit, I was impressed with Richard's vision and his plan to bring Ian Wilson and another Harrison postdoc, Jim Hogle, along to start up what was to be the first structural biology group at a biomedical research institute. When I asked him where my lab would be located, he pointed to the parking lot just north of his lab in the Immunology Building. “We're going to put a new lab building there, and you will have a great view of Torrey Pines Golf Course and the Pacific Ocean beyond,” he said. Richard was a compelling individual and his confidence impressed me enough to believe in his vision and join the effort. And so in late 1981 I started what I then called the “Molecular Graphics Lab.” After two or so years in a basement lab with no windows I moved into the newly constructed Molecular Biology building. His promise was kept, a wonderful view was restored and his vision for structural biology was realized. When Richard recruited me, I had not even thought to ask for a contract or start-up package. Nonetheless, he generously supported our structural biology efforts by acquiring Scripps's first computer used for research – a Digital Equipment VAX 750 with a whopping 2 MB of memory and a 20 MB disk. Moreover, he enabled the purchase of an Evans and Sutherland 3D interactive graphics system, similar to the one we used in Berkeley. In fact, this was an improved version, since it actually had color graphics. Richard did not hesitate to buy this expensive system (about $200,000 in 1981), even though, at the time, people considered a color system as a “frill.” Shortly after acquiring the system, Richard stopped by with Francis Crick in tow. To his thrill, I was able to show Crick an interactive 3D model of the tomato bushy stunt virus (TBSV), validating the nature of the virus structure he had proposed in the 1950s based on gene size and its geometric restrictions for viral capsid protein content. From the start, we were able to attract some great postdoctoral talent to Scripps. First to arrive was Michael Connolly, who, as a UCSF/UC Berkeley graduate student, had developed the first algorithm to compute and display the dot-based solvent-excluded molecular surface of protein structures. On his arrival he promptly started working on an improved version that could produce the actual analytical molecular surface geometry and enable more advanced visualizations resulting in a Science paper.6 Next to arrive were John Tainer and Libby Getzoff, who had recently solved the structure of Cu−Zn Superoxide dismutase at Duke University and were eager to calculate and visualize its electrostatic environment, which made it highly efficient in guiding the reactive oxygen species superoxide to the active site where it is disarmed. Our early collaborations with Richard involved using our newly developed computational and visualization approaches to analyze antigenicity and the function of antibodies, including designed catalysis.7-9 Whenever Richard casually dropped by my lab, he was like a kid in a candy shop looking and manipulating the latest structures. He was eager to expand our graphics capabilities in this pursuit. Through my and John and Libby's interactions utilizing early interactive graphics in the late 1970s we came to know Mike Pique, then a Computer Science graduate student at the University of North Carolina where he worked under Fred Brooks developing human-computer interfaces for molecular graphics. Mike was a graphics guru and shortly after John and Libby came to Scripps, we introduced Mike to Richard who hired him on the spot. Mike quickly started creating journal illustrations and cover images for many Scripps scientists (Figure 1), and soon Richard created a new position for Mike as the Scripps Director of Graphics Development. Figure 1Open in figure viewerPowerPoint A selection of some journal covers created by the Molecular Graphics Lab for Scripps researchers. a. Synthetic Vaccines21 – cover Art Olson; b. Atomic Mobility of Antigenic Sites7 – cover Libby Getzoff; c. Catalytic Antibodies22 – cover Art Olson; d. Zinc Finger Structure23 – cover Mike Pique; e. Catalytic antibodies24 – cover Mike Pique; f. Total Synthesis of D-enzyme23 – cover Art Olson; g. Self-assembling organic nanotubes25 – Art Olson; h. T-Cell Receptor Structure26 – cover Mike Pique; i. Nanoscale DNA Octahedron Synthesis27 – cover Mike Pique. Over the 1980’s, armed with state-of-the-art computing and visualization capabilities, I was able to produce a number of 16 mm movies that explained the structures of viruses as well as antibodies and enzymes. For many years these films were widely circulated, and fortunately for me attracted postdoctoral scientists who were focused on biomolecular structure and also with an interest in graphics. In 1987, David Goodsell joined my lab as a postdoc and subsequently developed the first version of our ligand docking code, AutoDock10 which has become the most widely used and cited tool of its kind, and graphical techniques for volume rendering11 and non-photorealistic rendering. Moreover, David's highly researched integration of biomolecular structure information into comprehensive and comprehensible illustrations of cellular scale molecular landscapes has changed our view of life's molecular machinery.12 As the popularity of our open source AutoDock code spread in the ‘90’s with more chemists and biologists using it and publishing, I was able to attract a young medicinal chemist to the lab, Stefano Forli. Stefano not only knew medicinal chemistry, but also knew the AutoDock code and had already contributed a new computational method to it. In the lab he continued to extend the capabilities of the code and has opened up new collaborations with Scripps chemists Jeff Kelley,13 Barry Sharpless14 and Ben Cravatt.15 Richard was a great cheerleader for our work, and thanks to his support over the years, we have impacted the trajectory of molecular graphics and molecular modeling in science and beyond. Through Richard's wide network of personal connections, he introduced me to a film producer, Eddie Garrick, who had been hired by the Walt Disney Company to produce a 3D Omnimax film for the GE Horizons pavilion in the forthcoming EPCOT Center in Florida. The film was part of a ride through a dome projecting the story of how the future of science was perceived through the ages. At that time in 1983, Garrick had decided that molecular graphics embodied the current view of the future of science, and I ended up creating that part of the immersive ride, a trip spiraling along the major groove of the double helix of DNA, and then being encapsulated by viral subunits. It played for over 15 years – with impacts that ranged from gleeful to dizzying. Richard was not only a visionary, but also a “rainmaker.” I was privileged to witness his persuasiveness and agility in brokering partnerships with corporate and other funding sources to enhance the capabilities of the Institute. For over 30 years, collaborations with companies enabled Scripps to grow continuously in both depth and breadth, expanding to cell biology, chemistry and neuroscience. While I wasn't privy to all the dealing that went on, I did participate in a few forays that Richard assembled to demonstrate Scripps’ capabilities. At one of these expeditions, at Sandoz Pharmaceuticals (which became part of Novartis) he met Michel Sanner, an applied mathematician and computer scientist who had mathematically characterized the molecular surfaces calculated by Mike Connolly's program allowing him to implement a blazingly fast surface calculation method that is still in use today in thousands of laboratories around the world.16 Richard immediately induced him to come work as a postdoc in my lab. Even the Scripps PhD program had its beginnings involving Richard's international diplomacy. His interest in synthetic malaria vaccines brought him into contact with Columbian immunologist Manuel Pataroyo. In 1985 Richard convinced Pataroyo to organize a scientific conference in Bogata. It was shortly after the attack on the Columbian Palace of Justice. During that meeting, Lerner actually signed a “treaty” with the President of Columbia, establishing a scientific and educational collaboration between that nation and Scripps. Those of us present at the Presidential Palace ceremony looked on in amazement – unsure of the implications, both scientific and political. In its course, there were no significant negative political repercussions, and it did lead to the first graduate student at Scripps Research, Hiro Aravelo, who after that meeting came from Columbia to Ian Wilson's lab and became Scripps's first PhD graduate. One of the most idiosyncratic of Richards′ inspirational moments arose from him connecting a toy I invented to a synthetic chemist. I had been exploring the visualization potential of the emerging 3D printing technology at the time and used the known structure of the poliovirus, which had been solved at Scripps, to develop a 3D-printed physical model of 12 polio viral pentamers that could, by random shaking, self-assemble into its intact viral capsid. It worked by complimentary magnets at the interfaces.17 One day when Richard dropped by the lab, I demonstrated the toy, and he loved it. He mentioned it to Udi Keinan, who was at Scripps at that time, inducing a meeting between us. In showing the model to Udi, we hypothesized that a similar mechanism could be designed at the atomic scale using pentagonal chemical building blocks. We came up with some corranuline-based models that launched an effort combining molecular dynamics and synthetic chemistry that resulted in a Lerner-communicated PNAS paper18 and Udi's subsequent work on self-assembling containers.19, 20 Richard's playfulness was another of his endearing characteristics that sparked inspiration and inventiveness in his colleagues.

We are excited to introduce the special issue of the Israel Journal of Chemistry dedicated to the awarding of the Wolf Prize in Chemistry 2022 to Benjamin Cravatt for his “contributions to understanding the chemistry of cellular communication and inventing chemical methodologies to study the role of carbohydrates, lipids, and proteins in such biological processes”. To celebrate Ben's countless achievements, we have invited several of his previous trainees, collaborators and colleagues to contribute to this special issue. With a focus on “Activity-based protein profiling”, this collection is designed to highlight the widespread impact of Ben's innovative chemoproteomic tools within chemistry, biology and pharmaceutical science. Activity-based protein profiling (ABPP) is a chemoproteomic method for the global analysis of protein function and protein-ligand interactions within native biological systems that was pioneered by the groups of Ben Cravatt and Matt Bogyo around the turn of the millennium.1, 2 This special issue, which aims to highlight the many different developments in this research field, begins with a perspective by Ben himself, providing an insightful personal account of past achievements, current applications and future directions in the field of ABPP (B. F. Cravatt, http://doi.org/10.1002/ijch.202300029). The article by Howard Hang, Ben's colleague at Scripps Research, provides an additional perspective on Ben's achievements and the sustained and continuous impact of Ben's research within the chemical biology community (H. C. Hang, http://doi.org/10.1002/ijch.202200066). The special issue continues with two broad review articles that give an overview of different facets of the field of activity-based protein profiling. In this context, Vinogradova and coworkers give a global overview of the tools, applications and translational potential of ABPP technologies with a focus on studying different states of proteins (K. A. Scott, T. L. Zhang, S. Y. Xi, B. Ngo, E. V. Vinogradova, http://doi.org/10.1002/ijch.202200101). Besides being able to study the activity of proteins globally, it is also highly desirable to elucidate effects based on different locations within the cell. Therefore, Moellering and coworkers focus on the discussion of the application of these technologies to illuminate the spatial regulation of protein activities within cells (C. S. Swenson, K. Smitha Pillai, A. J. Carlos, R. E. Moellering, http://doi.org/10.1002/ijch.202200104). In the further sections, the special issue focusses on the many different applications that are enabled by ABPP. Early developments in the ABPP field were largely focused on the development and application of fluorophosphonate (FP)-based and related probes for characterizing the serine hydrolase enzyme family. This research area continues to be a very active and fruitful application field for ABPP. The review article by Adibekian and coworkers highlights recent developments in serine hydrolase activity probes with a specific focus on the reactive groups used and their applications in understanding serine hydrolase function (B. Racioppo, N. Qiu, A. Adibekian, http://doi.org/10.1002/ijch.202300016). Furthermore, the review by Birner-Gruenberger and coworkers gives detailed insights into the application of these probes to study lipid hydrolases (S. E. Honeder, T. Tomin, M. Schinagl, R. Pfleger, J. Hoehlschen, B. Darnhofer, M. Schittmayer, R. Birner-Gruenberger, http://doi.org/10.1002/ijch.202200078). In the review article by van der Stelt and coworkers, the use of ABPP to further our understanding of the endocannabinoid system and to develop chemical compounds that modulate this system is highlighted (N. Zhu, A. P. A. Janssen, M. van der Stelt, http://doi.org/10.1002/ijch.202200115). Demonstrating the diverse application for ABPP and serine hydrolase profiling, Pezacki and coworkers provide an overview on the use of FP probes for understanding microRNA function during viral infection (P. Evers, J. P. Pezacki, http://doi.org/10.1002/ijch.202200088). The reviews on serine hydrolase profiling with ABPP are nicely complemented by two research articles. The first by Verhelst and coworkers describes the synthesis of an FP-alkyne ABPP probe and its further elaboration for dual color serine hydrolase labeling (J. Yang, D. Korovesis, S. Ji, J. P. Kahler, R. Vanhoutte, S. H. L. Verhelst, http://doi.org/10.1002/ijch.202200094). The second by Bachovchin and coworkers describes the elucidation of the substrate scope of the serine proteases DPP8/9 directly in the lysate of human cells (A. Bhattacharjee, D. A. Bachovchin, http://doi.org/10.1002/ijch.202200117). The demonstration of the utility of ABPP tools within the serine hydrolase family spurred the development of activity-based probes for a diverse array of protein families. The review by Breinbauer and coworkers describes the generation of ABPP tools to investigate oxidases and reductases with a special focus on the specific reactive groups that can be used to study these target families as exemplified by functional groups that are converted into electrophiles by oxidation (L. Krammer, R. Breinbauer, http://doi.org/10.1002/ijch.202200086). Furthermore, the review by Huang and coworkers focuses on tools to study glycan-binding and -processing proteins as well as glycosylated proteins (Z. Vilen, A. E. Reeves, M. L. Huang, http://doi.org/10.1002/ijch.202200097). Traditional activity-based probes rely on chemical probes that bind to specific proteins within a defined protein family. More recent work within the field also utilizes reactivity-based profiling, where proteins are grouped not by functional class, but by the presence of highly nucleophilic amino acids – a concept also pioneered by Ben's group with the isoTOP-ABPP platform.3, 4 Reactivity-based profiling has been widely utilized to study cysteine-mediated protein activities and Wang and coworkers provide a detailed review of the use of quantitative chemoproteomics in this context (W. Xiao, Y. Chen, C. Wang, http://doi.org/10.1002/ijch.202200100). These reactivity-based profiling tools have lately been expanded to many other amino acids beyond cysteine (for a review see e. g.5). As an example, Hsu and coworkers in their review provide an overview of profiling methods for reactive tyrosines within the proteome (J. W. Brulet, A. M. Ciancone, K. Yuan, K.-L. Hsu, http://doi.org/10.1002/ijch.202300001). One of the many important applications of ABPP is the ability to screen for inhibitors within a native proteome, thereby concurrently evaluating inhibitor potency and selectivity. These studies also routinely identify a multitude of new ligandable binding sites in proteins that are amenable to covalent ligands.4 Several reviews in this special issue summarize and provide future outlooks on the role of ABPP in ligand discovery. Parker and coworkers provide insight into fragment-based ligand and target discovery using many of the tools of ABPP as well as affinity- and reactivity-based profiling (I. Forrest, C. G. Parker, http://doi.org/10.1002/ijch.202200098). Additionally, Zhang and coworkers provide specific insights into case studies of covalent ligand discovery including traditional target-focused methods and global profiling against a complex proteome (C. Ngo, A. Ekanayake, C. Zhang, http://doi.org/10.1002/ijch.202200105). Marto and coworkers explicitly focus on the power of competitive ABPP and give some exciting case studies of covalent ligand discovery that were facilitated by ABPP and chemoproteomics (H. Zhu, M. Sharafi, W. Pin Teh, A. S. Bratt, S. J. Buhrlage, J. A. Marto, http://doi.org/10.1002/ijch.202200113). While many of the traditional ABPP probes modify protein active sites and, thereby, inhibit protein function, in a related method, known as ligand-directed chemistry, covalent protein labeling is directed by ligands to generate traceless protein modification without inhibiting the protein's function. This concept is discussed in the review by Hamachi and coworkers with a specific focus on the chemistries used and the biological applications (S. Sakamoto, I. Hamachi, http://doi.org/10.1002/ijch.202200077). To round up this ligand discovery section, a research paper by Bogyo and coworkers describes the synthesis of a library of cyclic peptides bearing fluorosulfate-based covalent warheads and the exploration of its targets in complex human proteomes (F. F. Faucher, D. Abegg, P. Ipock, A. Adibekian, S. Lovell, M. Bogyo, http://doi.org/10.1002/ijch.202300020). ABPP has also been broadly utilized to identify protein activities that are dysregulated in numerous disease states. One important application in this context is the use of ABPP to investigate protein activities in prokaryotic biology and during bacterial infections. The review article by Hatzios and coworkers focuses on the use of ABPP to study post-translational modifications and enzyme activities in the host during infection (R. Ramanathan, S. K. Hatzios, http://doi.org/10.1002/ijch.202200095). The review article by Chang and coworkers describes ABPP methods that allow studying protein functions in prokaryotic cells with a focus on bacterial physiology, pathogenesis and metabolism (K. P. Malarney, P. V. Chang, http://doi.org/10.1002/ijch.202200076). To round up this section, the review by Wright and coworkers discusses the application of ABPP to characterize bacteria in host-associated and environmental microbiomes (A. T. Wright, L. A. Hudson, W. L. Garcia, http://doi.org/10.1002/ijch.202200099). Together, this collection of contributions serves to highlight the diverse applications of ABPP in discovering new biology and developing new pharmacological tools. Besides his academic excellence, the impact and translational nature of Ben's research is additionally highlighted by the many pharmaceutical and biotech companies that he has advised and founded. The broad reach of Ben's science is undeniable, but his impact on science reaches well beyond his own research achievements. Ben has been a tremendous mentor to younger scientists throughout his career. His immense impact on training and inspiring younger scientists is underscored by the myriads of alumni from his lab now holding leading roles in both academia and industry. Ben's boundless energy and contagious enthusiasm for science has always inspired us and will continue to inspire us into the future. We are excited to honor the highly deserving recognition of Ben and his achievements through the Wolf Prize in Chemistry 2022 and hope that this issue celebrating his award provides a snapshot of everything that he has accomplished as well as a glimpse of the promising future that is yet to come.

1 Introduction The organometallic chemistry of zinc has witnessed a remarkable transition from Frankland's seminal work on diethyl zinc1 and the stoichiometric utilization of zinc in the Barbier2 and Reformatsky3 reactions towards the widespread application of zinc complexes as catalysts for a variety of valuable organic transformations.4 The high abundancy and hence low price of zinc paired with its low toxicity and good biocompatibility makes zinc catalysts an appealing alternative to expensive and (eco)toxic noble-metal complexes. As such, zinc complexes are used in various catalytic transformations such as C−C, C−N, and C−O bond formation,5 ring-opening (co)polymerization6 but also redox reactions.7 Furthermore, zinc is found in quite a number of naturally occurring enzymes, which inspired generations of bioinorganic and coordination chemists to develop new zinc(II) complexes aiming to mimic the active site of these potent biological catalysts, with carbonic anhydrase being one of the most powerful examples. In recent years, di- and polynuclear zinc complexes8 received particular interest as cooperative effects arising from the close proximity of two (or more) metal centres give rise to enhanced catalytic activity and selectivity.9 Bis(β-diketiminate)s10 have been identified as valuable ligand scaffolds as they are available by simple synthetic protocols and because the metal-metal interaction is readily tuned by adopting the terminal substituent and/or the bridging group. However, small variations in the ligand system may have substantial impact on the catalytic activity as for example illustrated in the ring-opening copolymerization of epoxides and CO211 as well as the ring-opening polymerization of caprolactone and derivatives.12 Furthermore, dinuclear zinc(II) bis(β-diketiminate) complexes have also been identified as potent catalysts for the borylation of aryl iodides13 and show interesting reactivity schemes towards oxygen.14 Inspired by these findings, we explored the impact of the bridging group and the terminal substituent on the synthetic accessibility of dinuclear zinc(II) complexes in which each zinc centre carries either an additional bis(trimethylsilyamide) or ethyl group.

The ability of B(C6F5)3, a Lewis super acid, to activate Si−H bonds through η1 coordination led to a numerous catalytic reduction processes.1 The first evidence of B(C6F5)3 Si–H bond activation was reported by Piers in the catalytic hydrosilylation of ketones and aldehydes.2 Using silicon-stereogenic hydrosilane as a stereochemical probe Rendler and Oestreich verified the nature of the Si−H bond activation step in the hydrosilylation of carbonyls.3 In 2014, the first structural evidence of such activation was accessed, in which highly Lewis acidic analog of B(C6F5)3, 1-boraindene and H−SiEt3 adduct (I−H−SiEt3) was synthesized, isolated and fully characterized (Figure 1).4 Figure 1Open in figure viewerPowerPoint Previously isolated of R3B−H−SiEt3 type complexes. The search for new main group Lewis super acids have recently brought the o-carborane (o-Cb) based substituents to light. o-Cbs are rigid, bulky, air- and moisture- stable, 3D aromatic, and extremely efficient electron withdrawing groups.5 As such, o-Cbs were used to stabilize various unique main-group and transition metal compounds.6, 7, 8, 9 The strong electron withdrawing ability of o-Cb based substituents was used for the synthesis of main-group based Lewis super acids that were used in activation of small-molecules.8c In 2019, Li and Wang reported a highly electrophilic o-Cb-substituted NHC-stabilized hydroborenium cation that formed a η2-σ-(H−Si)-complex (II−H−SiEt3) with HSiEt3 (Figure 1).10 Lin and Ye, in 2021, reported the o-Cb-based 9,10-diboraanthracene analogues, which were highly Lewis acidic, and as well formed a stable B−H−Si adduct (III−H−SiEt3) (Figure 1).11 Inspired by this chemistry, we decided to prepare a 3D analogue of 9-borafluorene,12 [1,1′-bis(o-carboranyl)]borane, (1) and see whether it forms a stable adduct with hydrosilanes. Noteworthy, during the work on this project, Ye and co-workers reported a series of [1,1′-bis(o-carboranyl)]boranes including 1-H-SiEt3 adduct (Figure 1), which was synthesized by the reaction of Et3SiH with a 1-Br in rather low yields (16 %).13 We report here an alternative synthesis of 1-H-SiEt3 in 85 % yields. As well as a detailed DFT investigation of the nature of B−H−Si interaction in 1-H-SiEt3 and preliminary reactivity studies of 1-H-SiEt3 with small molecules are shown. Also, its potential as catalyst in reactions between HSiEt3 and benzophenone is discussed. First, the synthesis of 1-Cl was attempted by the deprotonation of bis-o-carborane (CbH2) with nBuLi (2 equiv) in diethyl ether at 0 °C, followed by the addition of BCl3 in benzene and overnight reflux (Scheme 1). However, instead of the expected 1-Cl, 1-OEt was obtained quantitatively (Scheme 1). The formation of 1-OEt could be easily ascertained by the multinuclear NMR spectroscopy. Thus, the signals corresponding to the hydrogens (4.0 ppm) of CbH2 moiety in 1H NMR spectrum disappeared, while new quartet (4.44 ppm, J=8 Hz) and a triplet (1.41 ppm, J=8 Hz) signals that correspond to the EtO- group were measured. The 13C NMR spectrum of 1-OEt showed a shift (75.3 ppm) for the carbon (C-B) in comparison to the C−H moiety in CbH2 (55.0 ppm). A broad, signal at 36.29 ppm in 11B NMR spectrum clearly indicated a tricoordinated boron center. Finally, 1-OEt was successfully crystallized by slow evaporation from 1 : 3 mixture of hexane and benzene (Figure 2a). Scheme 1Open in figure viewerPowerPoint Synthesis of boron ethoxy complex (1-OEt) and its corresponding borohydride-silane complex (1-H-SiEt3). Figure 2Open in figure viewerPowerPoint POV-ray depiction of (a) 1-OEt and (b) 1-H-SiEt3.14 Thermal ellipsoids at the 50 % probability level, non-relevant hydrogens were omitted for clarity. The treatment of benzene solution of 1-OEt with an excess of Et3SiH at r.t. immediately led to the desired 1-H-SiEt3 which was purified and isolated by crystallization from pentane and benzene (1 : 3) in 85 % yields (for X-ray molecular structure see Figure 2b). In 1H NMR spectrum, new multiplet signal related to Et3Si moiety at δ=0.66-0.58 ppm was observed, and in 13C NMR two new signals at δ=6.47 and 5.45 ppm appeared. 29Si NMR showed a signal at δ=37.16 ppm. Overall, spectral data for 1-H-SiEt3 were in good agreement with previous report by Ye.13 Interestingly, there are structural differences in the X-ray molecular structure of 1-H-SiEt3 obtained by us compared to the previously reported structure by Ye,13 which could be the result of a higher crystal quality obtained in our case (Rfactor=4.74 % in our case compared to Rfactor=8.41 % in the previous case with a slight disorder in B−H−Si fragment13). For instance, Si1−H1 bond length in our case is longer than in a previously reported (1.635 vs. 1.620 Å, respectively) as well as B1−H1 bond length is shorter in our structure compared to previously reported (1.229 vs. 1.310 Å, respectively). While the most significant change is in the B1−H1−Si1 angle in 1-H-SiEt3 in our structure compared to the one reported by Ye13 (115.69° vs. 124.04°, respectively) that as a result leads to shorter B1⋅⋅⋅Si1 distance in our structure (2.435 vs. 2.588 Å). To get a deeper insight into the nature of bonding in 1-H-SiEt3, DFT calculations were performed at wb97xd/6-311 g(d,p) level of theory.15, 16 The calculated B1−H1 bond length (1.276 Å), B1⋅⋅⋅Si1 (2.347 Å), Si1⋅⋅⋅H1 (1.649 Å) distances and B1−H1−Si1 angle (106°) are close to the experimental values, and overall optimized structure of 1-H-SiEt3 is in good agreement with the molecular structure obtained in this work. The natural bond order (NBO) analysis revealed the presence of a delocalized 3c–2e bond between B1, H1 and Si1 centers. The high orbital coefficients at the H1 (0.7115) and B1 (0.5831) and a lower coefficient at Si1 (0.3920) indicate that major electron density of this 3c–2e bond resides on B1−H1 bond, and less on H1−Si1 bond. The calculated Wiberg bond indices (WBI) for 1-H-SiEt3 also showed a considerable interaction for B1−H1 (0.6630) and Si1−H1 (0.2882) bonds further indicating the 3c–2e bond nature of B−H−Si fragment. The atoms in-molecules (AIM) analysis of 1-H-SiEt3 showed a low electron density (ρ(r)) and a positive Laplacian at the bond critical points (BCP) for both B1−H1 and H1−Si1 bonds indicating donor acceptor type interactions between these centers (Figure 3). The absence of BCP between B1⋅⋅⋅Si1 centers shows that there is no bonding interaction between these two atoms. Figure 3Open in figure viewerPowerPoint AIM analysis of the optimized structure of 1-H-SiEt3. The successful preparation of 1-H-SiEt3 in high yields encouraged us to study its reactivity with small molecules. The reaction of 1-H-SiEt3 with an equivalent amount of sulphur (S8) in benzene led to the precipitation of colourless crystals, which were insoluble in common organic solvents that hampered their characterization by NMR. Nevertheless, the molecular structure of these crystals was determined by X-ray crystallography revealing the product of insertion of a sulphur atom into the B−H−Si fragment, 1-HS-SiEt3 (Scheme 2a; for molecular X-ray structure see Figure 4a). Scheme 2Open in figure viewerPowerPoint Reactivity of 1-H-SiEt3 with small molecules. Figure 4Open in figure viewerPowerPoint POV-ray depictions of (a) 1-HS-SiEt3 and (b) 1-CNBut.14 Thermal ellipsoids at the 50 % probability level, non-relevant hydrogens were omitted for clarity. The reaction of 1-H-SiEt3 with tertbutyl isocyanide (CNBut) led to the displacement of Et3SiH at boron center by CNBut and formation of 1-CNBut (Scheme 2b). The NMR data obtained after drying the reaction mixture clearly indicated the elimination of Et3SiH fragment (Figure S12–14). Finally, 1-CNBut was crystallized from benzene/toluene mixture (2 : 1), and its molecular structure was determined by X-ray crystallography (Figure 4b). The reaction of 1-H-SiEt3 with phenyl isocyanate, after 12 h, led to the formation of product 3 (Scheme 2c). 1H NMR of 3 showed a signal at 8.37 ppm that corresponds to N=C−H group with a corresponding signal at 161.6 ppm in 13C NMR spectrum. The formation of 3 can be explained by the silylation of oxygen in PhN=C=O followed by the addition of the B−H bond to the N=C double bond. Finally, 3 was crystallized from benzene and its molecular structure was determined using X-ray crystallography (Figure 5a). Figure 5Open in figure viewerPowerPoint POV-ray depiction of (a) 3 and (b) 4.14 Thermal ellipsoids at the 50 % probability level, non-relevant hydrogens were omitted for clarity. The N=C and C=O bond lengths (1.285 and 1.296 Å, respectively) suggest a doubly bonded nature of these bonds (Figure 5a). The sum of angles around C11 carbon center of 360° supports its sp2 hybridization. Thus, the molecular structure of 3 can be described as zwitterion, in which there is a formal negative charge on the B21 center, formal positive charge on Si1, and a formamide type moiety in between these two centers. Interestingly, upon purification of 3, a minute amount of different crystals was also obtained. These crystals were analyzed using X-ray crystallography and the molecular structure was determined as compound 4 (Figure 5b). Since 4 was not observed by NMR, it is likely that it is formed in trace amounts in the reaction between 1-H-SiEt3 and phenyl isocyanate (Scheme 2c). Interestingly, the reaction of 1-H-SiEt3 with benzophenone (5) in benzene led after 12 h at r.t. to diphenyl methane (6), triphenylmethane (7) (3 : 1, respectively) and the complimentary 1-OSiEt3 (Scheme 3a). The formation of both Ph2CH2 (6) (3.75 and 42.22 ppm) and Ph3CH (7) (5.42 and 57.18 ppm) could be easily observed in 1H and 13C NMR spectra (see ESI for reaction in C6D6). The formation of 7 could be explained by Friedel-Crafts reaction between silylated benzophenone cation [5-SiEt3]+ with benzene (Scheme 3b), while the complimentary anion [1-H2]− reacts with Wheland type intermediate generating H2 and 7-OSiEt3 and 1 (Scheme 3b). Afterwards 7-OSiEt3 transforms to the deoxygenated product 7 and 1-OSiEt3 via substitution of Et3SiO- group by a hydride from 1 (Scheme 3c). Importantly, intermediates 5-SiEt3 and 7-OSiEt3 could be observed in 13C-NMR spectra (δ=80.96 and 210.08 ppm, respectively) even after 30 min of the reaction, which indicates the extremely high hydridophilicity of the boron center in 1 that does not give up the hydride from the [1-H2]− easily. In hexane the same reaction produced only 6 after 4 days at r.t. (Scheme 3d). Scheme 3Open in figure viewerPowerPoint Reactivity of 1-H-SiEt3 with Ph2CO. The catalytic reactions between 5 and Et3SiH in presence of 1 mol % of 1-H-SiEt3 in hexane and benzene were also performed.17 However, both reactions led to the formation of hydrosilylation product (8) after 15 min (Scheme 4). The faster reactions in the catalytic run (Scheme 4) compared to rather slow stoichiometric reactions (Scheme 3) as well as formation of different products (6 and 7 in stoichiometric vs. 8 in catalytic reaction), suggest that the catalytic reactions do not follow the same mechanism as the stoichiometric ones, and are probably catalyzed by Et3Si+ cation generated during the reaction. Consequently, 1-H-SiEt3 serves as the pre-catalyst responsible for the initial delivery of the Et3Si+ cation, while [1-H2]− serves as a spectator counter anion (Scheme 4). Scheme 4Open in figure viewerPowerPoint Catalytic hydrosilylation of Ph2CO by Et3SiH. In conclusion, a B−H−Si η2-σ-complex (1-H-SiEt3) was prepared in excellent yields (>80 %) using a new route that involves the reaction of ethoxyborane 1-OEt with Et3SiH. Structural data and DFT computations suggest that the nature of B−H−Si bonding in 1-H-SiEt3 is a 3c–2e bond. The reactivity of 1-H-SiEt3 with small molecules showed that 1-H-SiEt3 is a good source of Et3Si+ cation, and rather bad hydride donor, which is the result of an extremely high hydridophilicity of 1. Catalytic hydrosilylation of benzophenone revealed that 1-H-SiEt3 in this reaction serves as the pre-catalyst responsible for supplying the initial Et3Si+ cation. We continue to study the chemistry of 1-H-SiEt3 and other o-Cb type substituents at different main group centers. Acknowledgments This work was supported by the Israeli Science Foundation, Grant 195/22.

1 Introduction Although by 1922, experimental evidence for the emerging quantum mechanics was both compelling and diverse (black-body radiation, optical and X-ray spectra, the photo-effect, heat capacity, the Franck–Hertz experiment, see, e. g., Ref. [1]), the molecular beam experiment of Stern and Gerlach (concluded on 8 February 1922) amounted to a much-needed confidence boost for quantum theory. Devised as a question posed to nature to decide between a classical and a quantum description of atomic behavior, the Stern–Gerlach experiment (SGE) ruled unequivocally in favor of the latter. In 1920–1921, when Otto Stern, Figure 1, conceived the idea for the SGE,6, 7 atomic behavior was epitomized by the 1916 Bohr–Sommerfeld–Debye quantum model of the atom.8-10 Stern expected that the SGE would prove this model wrong. After all, shortly after Niels Bohr published in 1913 the first sequel of his atomic model trilogy,8 Stern – and his close colleague and friend Max von Laue – took a vow,11 p. 74: “If this nonsense of Bohr should, in the end, prove to be right, we will quit physics.” Figure 1Open in figure viewerPowerPoint Otto Stern (1888–1969) was trained in Physical Chemistry by Otto Sackur2 at the University of Breslau and in Theoretical Physics by Albert Einstein[a] at the German University in Prague and at the ETH Zurich.3 In 1913, Stern became Privatdozent for Theoretical Physics at Zurich and in 1914, under Max von Laue's auspices, at the University of Frankfurt. In 1919, within Frankfurt's Institute for Theoretical Physics headed by Max Born, Stern launched his molecular beam method to examine the fundamental assumptions of theory that transpire in atomic, molecular, optical, and nuclear physics. Stern's experimental endeavors at Frankfurt (1919–1922), Hamburg (1923–1933), and, upon his forced emigration, in Pittsburgh (1933–1945) provided insights into the quantum world that were independent of spectroscopy and that concerned well-defined isolated systems, hitherto accessible only to Gedanken experiments. Apart from the SGE, Stern's seminal experiments include the threestage Stern–Gerlach experiment; experimental evidence for de Broglie's matter waves; measurements of the magnetic dipole moment of the proton and the deuteron; experimental demonstration of momentum transfer upon absorption or emission of a photon; the experimental verification of the Maxwell–Boltzmann velocity distribution via deflection of a molecular beam by gravity. In 1944, Otto Stern was awarded the 1943 Nobel prize in Physics (unshared) “for his contribution to the development of the molecular ray [beam] method and his discovery of the magnetic moment of the proton”. The official number of nominations provided by the Nobel Archives for Otto Stern is eighty-two, more than any other Physics Nobel laureate on public record. Thirty nominations were for the Stern–Gerlach experiment, fifty-two for Stern's other molecular beam work.4 For more on Stern, see Ref. [5]. [a] Stern's contact to Einstein was mediated by Sackur via Sackur's and Einstein's common colleague and friend Fritz Haber. Stern had invoked the molecular beam method once before, likewise with the aim to test the Old Quantum Theory (1900–1925). In his first beam experiment,12-14 Stern examined whether atoms possessed zero-point translational energy, whose existence had been previously hypothesized by Einstein and Stern as part of their attempt to explain the residual heat capacity of molecular hydrogen at low temperatures.15 Stern's 1920 experiment confirmed that thermal gaseous atoms in fact obey the classical Maxwell–Boltzmann distribution of velocities and yielded no evidence for translational zero-point energy. Only in 1927, it had been recognized that the residual heat capacity was due to nuclear spin which gave rise to the ortho and para allotropic modifications of molecular hydrogen.16, 17 The absence of the concept of spin, albeit electronic, is what would confuse and confound the interpretation of the SGE as well. However, a key quantum feature of the Bohr–Sommerfeld–Debye atom whose existence the SGE was designed to test – namely space quantization of electronic angular momentum – was robust enough to transpire independent of whether the electronic angular momentum was orbital or due to spin.

1 Introduction The behavior of group 14 A2H2 isomers has been of interest experimentally and computationally. Silicon is isoelectronic with carbon, but behaves very differently as a result of its larger, more flexible orbitals, making its study valuable.1-5 In silicon hydrides, the p-orbitals play a larger role in the bonding than they do in their carbon counterparts.1, 2 The ground state of C2H2 is of course a stable linear molecule with a C−C triple bond. However, Si−Si triple bonds were not identified until the early 2000s.6, 7 These Si−Si triple bonds are not found to be linear, but have been identified with trans structures rather than linear.6, 8-12 Goldberg et al first observed experimentally synthesized Sn−Sn double bonds that exhibited a trans-bent structure as a part of a larger analysis of several compounds, including A2R4 (A=Sn, Ge and R=CH(SiMe3)2).13, 14 In 1983 Lischka and Kohler predicted the global minimum of neutral Si2H2 to be an usual butterfly structure. This fascinating prediction was confirmed spectroscopically in 1991 in the remarkable experimental paper of Bogey, Bolvin, Demuynck, and Destombes.15 Some of the early theoretical studies on the neutral Si2H2 molecule predicted three main structures: the dibridged (butterfly), vinylidene-like, and trans.16, 17 The monobridged structure was later predicted and further studied by Colegrove, Grev, and Schaefer.18, 19 The monobridged structure of Si2H2 was confirmed in 1992 by a second remarkable microwave study by the Lille group.20 Numerous studies on silicon hydrides have shown that the lowest energy isomer of this structure is the butterfly structure,18, 19, 21-25 and above the butterfly are the monobridged, vinylidene-like, and finally trans as the highest energy.19, 23, 26 A2H2 structures similar to Si2H2 have also been studied extensively.27-32 All of these A2H2 analogues (where A can be Si, Ge, Sn, Pb, Al, Ga, and In) have similar minima including the trans, monobridged, and vinylidene-like isomers. Group 13 A2H2 molecules have planar dibridged structures as ground states.27-29 However, group 14 molecules show a butterfly structure as the ground state.18, 30-32 While these structures have been studied extensively, their cationic counterparts have received less attention. Si2H2+ has been briefly studied experimentally.33, 34 The goal of these studies was to find the heats of formation of several silicon hydrides including Si2H2+. The Si2H2+ heat of formation experimentally ranges from 268 kcal mol−1[33] to 290 kcal mol−1.34 Production of Si2H2+ has been experimentally synthesised as the neutral version loses an electron, or by Si2H4+ losing an H2 molecule.35 Photonic intensities were reported and analyzed to confirm that Si2H2+ was formed in these reactions. However, there is no experimental information concerning possible structures of Si2H2+. Computational studies that investigated Si2H2+ are found as long as 30 years ago using modest levels of theory. An important paper by Raghavachari in 1988 studied the cation at the unrestricted Hartree-Fock (UHF) level of theory, using the 6–31G* basis set.17 Raghavachari identified three minimum structures: the butterfly, vinylidene-like, and trans. Relative energies obtained from that study showed the butterfly as the ground state, with the vinylidene-like structure next lowest in energy and the trans structure much higher in energy. The next ab initio research to look into the cation was a paper by Curtiss and coworkers36 in 1991 who studied it at the Second-Order Møller–Plesset perturbation theory (MP2) with the 6–31G* basis set. In addition to the three structures Raghavachari identified, Curtiss found the monobridged structure as a minimum. Energies from that study reported the butterfly as the ground state, with vinylidene-like, monobridged, and trans all increasing in energy. In the present study, we used high level ab initio methods to analyze the differences between neutral and cationic Si2H2. We found the geometrical minima for both molecules, and compared them, in addition to analyzing the electronic structures and relative energies of all the isomers.

Bonnie L. Bassler, Ph.D. is the 2022 recipient of the Wolf Prize in Chemistry, a highly honored, prestigious award given to the world's foremost scientists. Among her colleagues, students, and trainees, Bonnie is known for her innate curiosity, shrewd mind, and exuberant personality that collectively distinguish her in the scientific world. Those of us that have been taught by Bonnie – whether in the lab, the classroom, or at her unique seminars – have learned much about communication and coordination by bacteria through chemical language. We describe here our collective journeys with Bonnie, and how these have shaped our careers and perspectives in science, as well as, how in our opinion Bonnie's work and personality has inspired researchers across disciplines to become interested in Bacterial Chemical Communication.

The synthetic accessibility of triarylcorroles allowed for the introduction of the corresponding coordination complexes with numerous elemental ions, of which the phosphorus corroles receive increasing attention.1 The reason is that they are very stable, have outstanding photophysical properties, and their axial ligands are easily modified.1b, 2 These features have been demonstrated to be very useful for quite different applications, ranging from photodynamic therapy and inactivation (PDT and PDI, respectively) to advanced photocatalytic processes.3 We now report how the photophysical variables and redox potentials may be tuned by focusing on the series of phosphorus complexes depicted in Scheme 1, which significantly differ in terms of the chelating corrole: three C6F5 on the meso-C atoms in 1-PL2 vs. three CF3 groups in 3-PL2, the eight Br atoms on the β-pyrrole positions in 2-P(OH)2, the dimeric (through β-pyrrole-C−C bonds) 4-PL2, and also by the identity of the phosphorus axial ligands- hydroxide vs. fluoride. Scheme 1Open in figure viewerPowerPoint Structures of the investigated phosphorus corroles. All the complexes presented in Scheme 1 were prepared according to literature reports,2a, 4 except of 4-P(OH)2 and 4-PF2. The former complex was prepared by treating pyridine solution of the free-base 45 with PCl3, followed by work-up, purification by column chromatography and analysis by various characterization techniques including X-ray crystallography. Treatment of 4-P(OH)2 by BF3⋅OEt2 solution led to its clean transformation to 4-PF2. Purity and identity of all the synthesized molecules were confirmed by routine spectroscopic and electrochemical techniques, fully described in the experimental section. X-ray diffraction of one of the crystals grown from the passive diffusion of n-hexane into a dichloromethane solution of 4-P(OH)2 confirmed its molecular structure: the bis-hydroxyphosphorus complex of the β-β’ linked dimer. The two phosphorus atoms reside almost in the same plane as the corrole rings, in slightly distorted octahedral geometries (Figure 1): four equatorial pyrrolic N atoms and two axial hydroxy O atoms. The O−P−O angle is about 180° and the P−O bonds (1.64–1.66 Å) are substantially shorter than the P−N bonds (1.82–1.86 Å) similar to the reported values of monomeric 1-P(OH)2.6 The two corrole rings are connected by a 1.49 Å long C−C bond, exactly matching with that of the free-base β-β’ linked dimer.5 The two corrole rings are oriented almost perpendicular to each other, with an angle of 89.1° between the two N4 planes. The distance between the two phosphorus atoms within the same molecule is 9.06 Å. Figure 1Open in figure viewerPowerPoint Molecular structure of 4-P(OH)2. Hydrogens atoms and solvent molecules are eliminated for the sake of clarity. Ellipsoids are drawn at 50 % probability. The motivation for the preparation of this series of compounds was to uncover how they differ in their absorption and emission maxima, as well as in redox potentials, and thereby explore important parameters that dictate the utility of such compounds for light induced processes.7 The first focus was on the elucidation of the oxidation potentials, which are doubtless macrocycle-centered, by recording the cyclic and square-wave voltammograms (Figure 2). Comparison of the three dihydroxyphosphorus complexes relative to 1-P(OH)2 (Table 1, entries 1–4) reveals that their halfwave redox potentials (E1/2) are all more positive, by: a) 410 mV upon bromination of all eight β-pyrrole positions (i. e., 2-P(OH)2); b) 220 mV when the meso-C-substituents are CF3 (in 3-P(OH)2) rather than C6F5; and c) 130 mV regarding the first redox potential of the corrole dimer 4-P(OH)2. The same trend, albeit less pronounced, is apparent for the difluorophosphorus complexes: 180 mV for CF3 (3-PF2) vs. C6F5 (1-PF2) and 60 mV for dimer (4-PF2) vs. monomer (1-PF2) (Table 1, entries 5–7). There are also large differences between the difluoro- and dihydroxy-phosphorus complexes of identical corroles (Table 1, entries 5 vs. 1, 6 vs. 3, 7 vs. 4), with the E1/2 values of the former being more positive by 200–270 mV. Figure 2Open in figure viewerPowerPoint Square-wave voltammograms with 25 Hz frequency of (a) difluorophosphorus complexes 1-PF2 (red), 4-PF2 (dark blue) and 3-PF2 (magenta) and (b) dihydroxyphosphorus catalysts: 1-P(OH)2 (green), 4-P(OH)2 (purple), 3-P(OH)2 (orange) and 2-P(OH)2 (blue). Potentials are versus Ag/AgCl and in the presence of 0.1 M TBAP and 0.5 mM substrate in acetonitrile. Table 1. UV/Vis (measured in acetonitrile) and fluorescence (measured in toluene) maximal wavelengths, redox potentials (in V, relative to Ag/AgCl)[a] and excited-state oxidation potentials of the phosphorus corroles. Entry Catalyst λmax/nm, ϵ×10-4 λmax/nm, ϵ×10-4 λmax/nm Emission HOMO-LUMO Gap (EeV)[b] E1/2 (V) Eo*oxd (V)[c] 1 1-P(OH)2 409, 44.6 581, 4.3 590, 647 2.13 1.04 −0.88 2 2-P(OH)2 428, 26.2 593, 2.7 605, 661 2.09 1.45 −0.43 3 3-P(OH)2 405, 25.1 568, 1.8 581, 633 2.18 1.26 −0.70 4 4-P(OH)2 410, 34.8 421, 31.4 594, 10.0 625, 692 2.07 1.17, 1.26 −0.63 5 1-PF2 399, 49.3 567, 2.9 578, 632 2.19 1.31 −0.65 6 3-PF2 397, 28.2 561, 1.8 574, 625 2.21 1.49 −0.49 7 4-PF2 402, 43.8 414, 49.6 580, 12.5 592, 650 2.12 1.37, 1.45 −0.54 [a] Halfwave potentials (E1/2) values were determined by cyclic voltammetry of 0.5 mM solutions of phosphorus corrole in acetonitrile containing 0.1 M TBAP and the following electrodes: working: glassy carbon, reference: Ag/AgCl, counter: Pt wire. [b] EeV=1240/λ(nm) where λ is the Q-band wavelength. [c] Eo*oxd=Eooxd−E0,0, where Eo*oxd is the oxidation potential of the excited state species, Eooxd is the oxidation potential of the ground state using electrochemical measurements. E0,0 is the zero–zero excitation energy estimated from the fluorescence (E0,0 = ES) spectra. ES=[1240/(λmax(onset) in nm)] where λ is the fluorescence wavelength. All the phosphorus corrole complexes display absorption maxima in the range of 397–428 nm (Figure 3). The phosphorus corroles (both monomers and dimers) with axial fluorides absorb at a slightly higher energy than those with axial hydroxy groups, coming into effect by 7–10 and 7–12 nm shorter λmax values in the near-UV (Soret) and visible (Q) bands, respectively; and the emission spectra are affected in a qualitatively similar fashion. The absorption maxima are shifted to lower energies in the brominated derivative 2-P(OH)2, by 19 nm relative to 1-P(OH)2. A final note is that the dimers, 4-P(OH)2 and 4-PF2, absorb the longest wavelengths and also with the largest efficacies. This as is evident by the molar absorption coefficient (ϵ) values of the most intense Q-bands: 100,000-125,000 vs. 29,000-43,000 M−1cm−1 of the monomers. Figure 3Open in figure viewerPowerPoint Comparison of the spectral features in the absorption spectra at (a) Soret bands, and (b) Q-bands of the various phosphorus corroles, at identical concentrations (1.7 μM) in acetonitrile. The thus acquired experimental data allows for determination of two values that are important for the utility of the compounds: HOMO-LUMO gaps and excited-state redox potentials. Approximate (i. e., by ignoring electron-electron interaction)8 HOMO-LUMO gaps were found to vary only little, between 2.07 and 2.21 V. But the oxidation potentials of the excited-state (Eo*oxd ) display quite a wide range of values between −0.88 and −0.43 V (Table 1, last columns). Upon photoexcitation of phosphorus corroles in the presence of a suitable electron acceptor strongly oxidizing cationic phosphorus corrole will be produced. One important conclusion is that when photosensitizers with large oxidative power are required, such as for chlorination of organic compounds by HCl rather than by Cl2,9 a good strategy would be to focus on the tris-CF3-substituted corrole and placing electron-withdrawing axial ligands on the chelated phosphorus. This may be exemplified by 3-PF2, whose ground-state oxidation potential is E1/2=1.49 V, which is even more than what can be achieved via bromination of 1-P(OH)2 to 2-P(OH)2 (E1/2=1.45 V). Another conclusion is that the two corrole subunits present in complexes 4-P(OH)2 and 4-PF2 are interacting despite of being connected by only a single C−C bond and the unfavorable angle between them regarding through space interaction between the two π-systems. This comes into play by the first redox potential being different by 60–130 mV relative to the corresponding monomers 1-P(OH)2 and 1-PF2 and, more so by virtue of displaying two redox processes rather than only one. Their 80–90 mV difference between the first and second oxidation potential may be compared with the 18–23 mV differences in redox potentials obtained in bimetallic complexes wherein the corrole subunits are joined by two C−C bonds and are practically coplanar.10 Ongoing studies are focused on utilizing the acquired knowledge for introducing these and related complexes as photocatalysts. Experimental Section Materials and Methods Tetrabutylammonium perchlorate was purchased from Sigma Aldrich. The solvents utilized for electrochemistry and spectroscopic studies were of HPLC grade. 1H NMR, 19F NMR and 31P NMR were recorded on a Bruker Advance III 400 spectrometer (operating at 400.4 MHz for 1H 376.7 MHz for 19F and 162 MHz for 31P). Chemical shifts have been reported in ppm with respect to the signals from the residual hydrogen atoms in CDCl3. Absorption spectra were recorded on a Cary 8454 UV-Vis spectrometer by Agilent Technologies. Emission spectra were measured using a spectrofluorometer from Edinburgh Instruments FS5 equipped with a Xenon-arc lamp. Electrochemical measurements were performed by using a combination of three electrodes: Glassy carbon (working electrode), Platinum wire (counter electrode) and Ag/AgCl (reference electrode) in EMStat3+electrochemical system. Single crystal of 4-P(OH)2 was dipped in Paratone-N oil and mounted on a APEX2 (Bruker AXS) diffractometer. The crystal was kept at 200.15 K during data collection. Using Olex2,11 the structure was solved with the olex2.solve12 structure solution program using Charge Flipping and refined with the SHELXL13 refinement package using Least Squares minimisation. Synthesis of 4-P(OH)2 4-P(OH)2 was prepared by following a similar procedure as reported earlier by our group2a by starting with the free-base corrole dimer 4.5 Pure crystalline compound was isolated after extraction, purification by column chromatography and recrystallization from CH2Cl2 : n-hexane. 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 2H), 9.57 (d, J=4.3 Hz, 2H), 9.09 (d, J=3.1 Hz, 2H), 9.05 (d, J=4.5 Hz, 2H), 8.83 (d, J=4.8 Hz, 2H), 8.64 (d, J=4.7 Hz, 2H), 8.50 (d, J=4.1 Hz, 2H), −4.36 (d, J=5.4 Hz, 2H), −4.46 (d, J=5.6 Hz, 2H) (Figure S1). 19F NMR (377 MHz, CDCl3) δ −134.08 (dd, J=24.8, 7.6 Hz, 2F, ortho-F), −136.24 (s, 2F, ortho-F), −136.44–−136.95 (m, 8F, ortho-F), −151.55 (t, J=20.9 Hz, 2F, para-F), −151.83 (t, J=20.9 Hz, 2F, para-F), −153.45 (t, J=21.1 Hz, 2F, para-F), −160.95–−161.18 (m, 4F, meta-F), −161.32 (qd, J=22.8, 8.3 Hz, 4F, meta-F), −162.60–−162.86 (m, 2F, meta-F), −162.96–−163.26 (m, 2F, meta-F) (Figure S2). 31P NMR (162 MHz, CDCl3) δ −189.98 (s) (Figure S3). UV-Vis (Toluene): λmax (ϵ x 10−4)=416 nm (28.4), 427 nm (25.2), 570 nm (3.9) and 598 nm (8.1). Synthesis of 4-PF2 A sample of 4-P(OH)2 (20 mg, 11.7 μmol) was dissolved in a minimum volume of CH2Cl2 under inert atmosphere. Then an excess of BF3⋅OEt2 solution (100 μL) was added dropwise and the reaction was stirred for 30 min. Excess of BF3⋅OEt2 was slowly quenched and after solvent extraction, the crude product was subjected to purification by column chromatography (silica gel). The desired complex was collected upon elution with a solvent mixture of CH2Cl2 : n-hexane (70 : 30). Pure complex, 4-PF2 (6 mg, 30 %) was obtained upon recrystallization using CH2Cl2 : n-hexane. 1H NMR (400 MHz, CDCl3) δ 10.05 (t, J=3.1 Hz, 2H), 9.68 (t, J=4 Hz, 2H), 9.21 (t, J=4.4 Hz, 2H), 9.16 (t, J=4.7 Hz, 2H), 8.93 (t, J=4.3 Hz, 2H), 8.75 (t, J=4.3 Hz, 2H), 8.60 (t, J=4.8 Hz, 2H) (Figure S4). 19F NMR (377 MHz, CDCl3) δ −35.14 (d, J=17.1 Hz, 1F), −37.31 (d, J=15.9 Hz, 1F), −39.22 (t, J=16.9 Hz, 1F), −41.40 (t, J=16.1 Hz, 1F), −134.21 (dd, J=24.6, 7.4 Hz, 2F, ortho-F), −135.63 (d, J=23.3 Hz, 2F, ortho-F), −135.95 (d, J=22.6 Hz, 2F, ortho-F), −136.13 (d, J=23.9 Hz, 2F, ortho-F), −136.39 (dd, J=31.3, 26.8 Hz, 4F, ortho-F), −150.73 (t, J=20.9 Hz, 2F, para-F), −150.98 (t, J=20.9 Hz, 2F, para-F), −153.21 (t, J=20.7 Hz, 2F, para-F), −160.38–−160.92 (m, 8F, meta-F), −161.89– −162.07 (m, 2F, meta-F), −162.44 (t, J=22.6 Hz, 2F, meta-F) (Figure S5). 31P NMR (162 MHz, CDCl3) δ −176.32 (s), −181.36 (s), −186.43 (s) (Figure S6). UV-Vis (Toluene): λmax (ϵ x 10−4)=408 nm (31.7), 420 nm (34.1), 565 nm (4.4) and 586 nm (8.9). Acknowledgments This research was supported by the Israel-India Ministries of Science and Technology (ZG).

Introduction Many experimental gas-phase and solution studies have been performed on the reactivity of aromatic carbon-centered σ-type biradicals, including the three benzynes.1-3 The meta-benzyne analogs are especially interesting as their radical reactivity can be tuned from nonexistent to dominant by minor structural changes, such as addition of a cyano or a hydroxyl group in a specific position.4, 5 The analogous tri- and tetraradicals containing one or more meta-benzyne moieties are even more fascinating due to their complex electronic structures. Indeed, some theoretical studies have been published on this type of tri- and tetraradicals.6 However, difficulties in studying the above compounds experimentally, including their clean generation in solution, has limited these studies to only two such triradicals (2,4,6-tridehydro- and 3-hydroxy-2,4,6-tridehydropyridinium cations) and two tetraradicals (2,4,6-tridehydropyridine radical cation and 2,4,6,8-tetradehydroquinoline; 2 in Figure 1) studied in the gas phase by using mass spectrometry.7-10 Examination of the reactivity of the 2,4,6-tridehydropyridinium cation revealed that this compound is best described as a reactive monoradical with a substantially less reactive, strongly coupled biradical moiety (meta-pyridyne).7, 8 Substituents in this triradical were found to influence its reactivity through inductive effects. For example, an electron-donating substituent (3-hydroxy−) between two of the unpaired electrons increased the coupling within this meta-benzyne moiety, converting it completely unreactive.7, 8 Figure 1Open in figure viewerPowerPoint The tetra- (1 and 2), bi- (3–6) and monoradicals (7–12) studied. As opposed to the triradicals,7, 8 a tetraradical, the 2,4,6-tridehydropyridine radical cation, was found not to undergo radical reactions.9 Due to resonance, this tetraradical is best described as a highly electrophilic carbocation with a delocalized and therefore unreactive meta-benzyne moiety. It readily reacts with nucleophiles to yield relatively unreactive meta-benzyne products.9 Examination of the reactivity of the 2,4,6,8-tetradehydroquinolinium cation (2) revealed, surprisingly, that the relatively strong spin-spin coupling between the radical sites at C-4 and C-8 weakens the coupling between the other radical sites (meta-benzynes; C-2 and C-4 as well as C-6 and C-8), which results in greater than expected radical reactivity for the meta-benzyne moieties.10 We report here an investigation on a new tetraradical system that also only contains meta-benzyne moieties, the 2,4,5,7-tetradehydroquinolinium cation (1 in Figure 1), and comparison of its chemical properties to those of 2. Our experimental approach involved preparing the tetraradical in the gas phase from a protonated tetraiodoprecursor by using CAD to induce four consecutive C−I bond homolysis reactions and then examine the reactions of the tetraradical cation toward different reagents to probe its reactivity.

1 Introduction The chemistry of Ig-mediated catalysis is based on the initial proposal of Linus Pauling, who wrote that catalytic activity of an antibody molecule might be achieved through its preferential stabilization of the transition state (TS) of the chemical reaction.1 That was followed by the anti-idiotypic network concept of the immune system proposed by Niels Ernie.2 Numerous experimental data of the last three decades has supported the validity of these hypotheses. These two proposals may explain, in part, the appearance of naturally occurring immunocatalysis in pathology of human and animal models of disease. Unfortunately, Fisher's Lock& Key theory3 as well as Pauling's TS theory4 have serious conceptual limitations that limit the improvement of kinetic parameters for immunocatalysis. These limitations arise from the need to provide appropriate dynamics of an Ig template to eliminate reaction products and effectively to simulate several TS niches. Effective catalysis requires an unusual configuration of the amino acids that make up CDRs. This requires the functional analysis of millions, rather than hundreds, of antibody clones. Such obstacles were overcome in part by the pioneering implementation of combinatorial chemistry together with high throughput screening technologies. Indeed, selection from an extraordinarily large collection of Ig templates increases the likelihood that antibodies with the proper configuration of an active center can be isolated.5 Single B cell selection using microfluidic technology;6 combinatorial library screening of highly representative libraries;7 machine learning (ML) and structural computing;8 quantum mechanics/molecular mechanics (QM/MM) calculations and purely robotic procedures are used for the elaboration of more effective immunoglobulin-derived catalytic templates,9 ultimately leading to development of therapeutic antibodies with catalytic function and catalytic Chimeric Antigen Receptors (catCARs) with tunable pharmacokinetic parameters.10

Introduction Infections with multidrug-resistant bacteria are a growing health care concern, recently coined as a ‘silent pandemic’.1 Antimicrobial resistance does not only impair chances of a successful cure of patients with community-acquired infections, but also puts achievements of modern medicine such as chemotherapy, organ transplantations or other procedures associated with increased infection susceptibility at risk. The problem is exacerbated by a thin, overall insufficient pipeline of novel, resistance-breaking antibiotics.2 This is particularly true for Gram-negative pathogens, which have an asymmetric outer membrane with a distinct chemical composition that is impermeable for most small ‘drug-like’ molecules. To gain a more profound scientific understanding of bacterial translocation has been the subject of intense research efforts, as a prerequisite to find treatment solutions.3 One rational approach deals with targeting one of the entrance gates for nutrients of Gram-negative bacteria in a Trojan-Horse strategy (Figure 1):4 Ferric iron is essential for bacterial growth, but notoriously scarce in vivo due to the low solubility of the metal and competing iron storage systems of the host.5 Therefore, bacteria biosynthesize siderophores, low molecular weight ligands with a high affinity for iron that are secreted into the environment, and actively re-imported into bacteria as holo-complexes.6 By conjugating an antibiotic to the siderophore, a toxic cargo can be smuggled into the pathogen. The success and clinical relevance of this strategy has been recently proven with the launch of cefiderocol (mind the tradename: ‘FeTroja’), a catechol-conjugated cephalosporin.7 Figure 1Open in figure viewerPowerPoint Iron uptake into Gram-negative bacteria and Trojan horse strategy. A) Mechanism of siderophore-mediated iron uptake and its use in Trojan horse conjugates. The siderophore is depicted as a black closed or open circle, and the drug as a grey-red ellipse. B) Structures of 1, 2, and 3. Iron-binding hydroxamates are shown in red, the DOTAM core in blue, and the antibiotic moiety in green. We have embarked on designing artificial siderophores as Trojan Horses, which are featured by advantages such as tunable iron binding motifs, which translates in altered bacterial selectivity, a scalable and efficient synthetic access, and high stability.8 In particular, the 1,4,7,10-tetraazacyclododecane core, further functionalized to a DOTAM binder (Figure 1), has turned out to be a versatile scaffold for the accommodation of various antibiotics or imaging moieties, that have also been combined to full theranostics.9 DOTAM-based siderophores proved their functionality in vivo by the imaging of infections in mice by optical as well as positron emission tomography (PET) readouts.9a, 10 So far, we have employed only catechol motifs as iron binders due to their high affinity for the metal; however, they proved to be inferior to linear hydroxamates for the detection of bacteria-triggered chemiluminescent signals due to quenching effects of the catechols.8a Furthermore, mechanisms of the innate immune system to inactivate natural catecholate siderophores have been reported,5, 11 and their potentially unspecific binding capabilities towards off-targets constitute further, albeit theoretical concerns. Hydroxamates, on the other hand, have been applied successfully in a variety of siderophore conjugates.4a, 12 For these reasons, the present study aimed at introducing hydroxamates instead of catechols at the established DOTAM core. The synthesis and the biological characterization of a [3+1]-substituted DOTAM, substituted with three hydroxamate arms for iron binding and a fourth for the attachment of an antibiotic, is described in the following.