The site-selective formation of carbon-carbon bonds through direct functionalizations of otherwise unreactive carbon-hydrogen bonds constitutes an economically attractive strategy for an overall streamlining of sustainable syntheses. In recent decades, intensive research efforts have led to the development of various reaction conditions for challenging C-H bond functionalizations, among which transition-metal-catalyzed transformations arguably constitute thus far the most valuable tool. For instance, the use of inter alia palladium, ruthenium, rhodium, copper, or iron complexes set the stage for chemo-, site-, diastereo-, and/or enantioselective C-H bond functionalizations. Key to success was generally a detailed mechanistic understanding of the elementary C-H bond metalation step, which depending on the nature of the metal fragment can proceed via several distinct reaction pathways. Traditionally, three different modes of action were primarily considered for CH bond metalations, namely, (i) oxidative addition with electronrich late transition metals, (ii) σ-bond metathesis with early transition metals, and (iii) electrophilic activation with electrondeficient late transition metals (Scheme 1). However, more recent mechanistic studies indicated the existence of a continuum of electrophilic, ambiphilic, and nucleophilic interactions. Within this continuum, detailed experimental and computational analysis provided strong evidence for novel C-H bond metalationmechanisms relying on the assistance of a bifunctional ligand bearing an additional Lewis-basic heteroatom, such as that found in (heteroatom-substituted) secondary phosphine oxides or most prominently carboxylates (Scheme 1, iv). This novel insight into the nature of stoichiometric metalations has served as stimulus for the development of novel transformations based on cocatalytic amounts of carboxylates, which significantly broadened the scope of C-H bond functionalizations in recent years, with most remarkable progress being made in palladiumor ruthenium-catalyzed direct arylations and direct alkylations. These carboxylate-assisted C-H bond transformations were mostly proposed to proceed via a mechanism in which metalation takes place via a concerted base-assisted deprotonation. To mechanistically differentiate these intramolecular metalations new acronyms have recently been introduced into the literature, such as CMD (concerted metalationdeprotonation), IES (internal electrophilic substitution), or AMLA (ambiphilic metal ligand activation), which describe related mechanisms and will be used below where appropriate. This review summarizes the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010. Moreover, experimental and computational studies on stoichiometric metalation reactions being of relevance to the mechanism of these catalytic processes are discussed as well. Mechanistically related C-H bond cleavage reactions with ruthenium or iridium complexes bearing monodentate ligands are, however, only covered with respect to their working mode, and transformations with stoichiometric amounts of simple acetate bases are solely included when their mechanism was suggested to proceed by acetate-assisted metalation.

Carboxylate-assisted transition-metal-catalyzed C-H bond functionalizations: mechanism and scope.

Asymmetric enamine catalysis.

The selective transformation of ubiquitous but inert C–H bonds to other functional groups has far-reaching practical implications, ranging from more efficient strategies for fine chemical synthesis to the replacement of current petrochemical feedstocks by less expensive and more readily available alkanes. The past twenty years have seen many examples of C–H bond activation at transition-metal centres, often under remarkably mild conditions and with high selectivity. Although profitable practical applications have not yet been developed, our understanding of how these organometallic reactions occur, and what their inherent advantages and limitations for practical alkane conversion are, has progressed considerably. In fact, the recent development of promising catalytic systems highlights the potential of organometallic chemistry for useful C–H bond activation strategies that will ultimately allow us to exploit Earth's alkane resources more efficiently and cleanly.

Understanding and exploiting C–H bond activation

The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

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Mechanochemistry: opportunities for new and cleaner synthesis

The increase in atmospheric carbon dioxide is linked to climate changes; hence there is an urgent need to reduce the accumulation of CO2 in the atmosphere. The utilization of CO2 as a raw material in the synthesis of chemicals and liquid energy carriers offers a way to mitigate the increasing CO2 buildup. This review covers six important CO2 transformations namely: chemical transformations, photochemical reductions, chemical and electrochemical reductions, biological conversions, reforming and inorganic transformations. Furthermore, the vast research area of carbon capture and storage is reviewed briefly. This review is intended as an introduction to CO2, its synthetic reactions and their possible role in future CO2 mitigation schemes that has to match the scale of man-made CO2 in the atmosphere, which rapidly approaches 1 teraton.

The teraton challenge. A review of fixation and transformation of carbon dioxide

Inside Cover: Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Umpolung 1,4-Addition of Aryl Iodides to Enals (Angew. Chem. Int. Ed. 1/2020)

We have found that the bisamides Cp 2 Zr(NHR) 2 (1) catalyze the hydroamination of alkynes and allene and have investigated the scope and mechanism of this proces. Examining both catalytic and stoichiometric additions of 2,6-dimethylalanine to diphenylacetylene in the presence of the corresponding zirconium bisamide 1a at 95 o C indicates that the reaction is first order in the concentration of bisamide and alkylene and inverse first order in amine

Stoichiometric and catalytic hydroamination of alkynes and allene by zirconium bisamides Cp2Zr(NHR)2

Generation, alkyne cycloaddition, arene carbon-hydrogen activation, nitrogen-hydrogen activation and dative ligand trapping reactions of the first monomeric imidozirconocene (Cp2Zr:NR) complexes

In an age when organic chemists have shown that even the most complex natural and unnatural products can be synthesized,1-3 the emphasis of synthetic chemistry is shifting to how they can be assembled in a truly practical fashion.4-6 A pressing challenge facing organic chemists, therefore, is to advance new processes that are not only efficient, selective, and high yielding, but that are also environmentally friendly.7,8 Historically, the metric of reaction success has been the yield. Although yields will remain imperative, alternative measures are the ‘greenness’ of a reaction, or E factor,9 and the volume productivity.10 The E factor, introduced by Sheldon,9 is defined as the ratio of weight waste to weight product while the volume productivity is the grams product per liter of reaction medium. The E factor for many pharmaceuticals has been estimated to exceed 100.11,12 The largest contributors to the magnitude of E factor are organic solvents, many of which are ecologically harmful and require expensive remediation.

As global environmental legislation becomes stricter, consideration of environmental concerns must be addressed at early stages of product development. By doing so, project cost reduction of 50% or more have been realized.13 Although steps toward sustainability can be made by reusing solvents, rarely is recycling accomplished with complete efficiency. An alternative strategy to reduce the E factor of reactions and their impact on the environment is to conduct them under solvent-free conditions.11,14-16 Among the benefits of solvent-free processes are cost savings, decreased energy consumption, reduced reaction times, and a large reduction in reactor size and capital investment. As a result, introduction of solvent-free reactions, including solvent-free polymerizations,14,17-20 radical additions,14,21-24 ionic reactions,25-31 solid state reactions15,32-34 and photochemical reactions15,35-37 has increased steadily in recent years. Solvent-free catalytic enantioselective reactions, however, have received much less attention.

The paucity of catalytic asymmetric solvent-free reactions is not unexpected. Catalyst efficiency and enantioselectivity is frequently highly sensitive to the nature of the solvent.38 Examples in which a catalyst can generate enantiomeric products with high levels of enantioselectivity in different solvents have been reported.39 Moreover, enantioselectivities are often dependent on catalyst concentrations. Consequently, two of the most important variables for catalyst optimization, solvent properties and concentration, are eliminated under solvent-free conditions. Furthermore, under solvent-free conditions the reaction medium will change as reagents and substrates are converted to products. The impact of such changes is currently unpredictable, complicating reaction development. We believe that these limitations have dissuaded many investigators from considering solvent-free catalytic asymmetric reactions. The potential environmental benefits and the economic incentive, however, have created significant demand for such processes.

In response to these challenges, an increasing number of research groups are developing asymmetric catalysts for use under solvent-free or highly concentrated reaction conditions. The results of these studies have been mixed. In some cases, catalysts that demonstrate excellent enantioselectivity and activity under standard solvent conditions exhibit lower selectivity in the absence of solvent. In contrast, other catalysts react with excellent levels of enantioselectivity and greatly increased activity, enabling significant reductions in catalyst loading under solvent-free conditions.

The potential advantages of asymmetric catalysis under solvent-free and highly concentrated reaction conditions have inspired this review. In turn, it is hoped that a comprehensive compilation of reports in this area will stimulate further investigations into solvent-free catalytic asymmetric reactions.

A significant body of research has been published concerning solvent-free organic synthesis and the subject has been reviewed.10,11,14,15,40 Solvent-free asymmetric catalysis, however, is a relatively new area and we are not aware of reviews devoted to this topic. This review will cover small molecule catalyzed enantioselective reactions under solvent-free or highly concentrated reaction conditions up to the end of 2006. Additionally, we will include reactions of enantioenriched substrates with enantioselective catalysts in which the diastereoselectivity is catalyst controlled (not substrate controlled). We define solvent-free reactions as those employing less than five equivalents of one reagent with respect to the substrate. The definition of highly concentrated reaction conditions used herein is those that utilize less than 5 equivalents of solvent with respect to the substrate.

Despite amazing advances in chemistry database coverage, technology, and search engines, there are no straightforward ways to search the literature for ‘highly concentrated catalytic asymmetric reactions’. Even reactions performed in the absence of solvent do not always contain the key words ‘solvent-free.’ The citations included herein come from extensive literature searches, scouring experimental sections and supporting information, and personal knowledge. Nonetheless, our apologies are extended to those who have made contributions in this area but whose work we missed.

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Patrick J. Walsh

Papers

Inside Cover: Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Umpolung 1,4-Addition of Aryl Iodides to Enals (Angew. Chem. Int. Ed. 1/2020)

Stoichiometric and catalytic hydroamination of alkynes and allene by zirconium bisamides Cp2Zr(NHR)2

Generation, alkyne cycloaddition, arene carbon-hydrogen activation, nitrogen-hydrogen activation and dative ligand trapping reactions of the first monomeric imidozirconocene (Cp2Zr:NR) complexes

A Green Chemistry Approach to Asymmetric Catalysis: Solvent-Free and Highly Concentrated Reactions

Monomeric and dimeric zirconocene imido compounds: synthesis, structure, and reactivity