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Scheme 7. Reductive addition of elemental lithium (Schlenk-Addition) or alkyllithium (Ziegler-Addition, carbometalation) to C-C double bonds of alkenes.
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The element lithium has been discovered 200 years ago. Due to its unique properties it has emerged to play a vital role in industry, esp. for energy storage, and lithium-based products and processes support sustainable technological developments. In addition to the many uses of lithium in its inorganic forms, lithium has a rich organometallic chemi...
Citations
... Pioneered by Wilhelm Schlenk in 1917, organolithium reagents drastically elevated their role in synthetic chemistry over the past hundred years and solidified their position among the most versatile and widely used reagents in organic synthesis. [1][2][3][4][5] The reason of such prosperity is a low cost, the simplicity of handling (operations at temperatures of liquid ammonia or dry ice under argon atmosphere are a common practice nowadays) and generally clean, selective and high-yielding reactivity. Solvents used in organolithium chemistry are typically mixtures of low-boiling alkanes and ethers, which can be removed in an energy-efficient way by distillation. ...
Non‐covalent interactions such as coordination of an organolithium reagent by a directing group and steric repulsion of substituents strongly affect the halogen‐lithium exchange process. Here we present the manifestation of the “buttressing effect” – an indirect interaction between two substituents issued by the presence of a third group – and its influence on the ease and selectivity of the bromine‐lithium exchange and the reactivity of formed aryllithiums. The increase of the size of the “buttressing” substituent strongly affects the conformation of a NMe2 group, forcing it to hinder ortho‐bromine and thus slowing down the exchange. In naphthalene substrates bearing two bromines, this suppresses regioselectivity of the reaction. The “buttressing effect” forces formed aryllithiums to deaggregate, thus boosting their reactivity. This facilitates the decomposition via protolisys by ethereal solvents even at low temperatures and in some cases initiates fast Wurtz‐Fittig coupling.
... Lithium (Li) is an alkali metal naturally found in soil and water. Li has various industrial and commercial applications, such as being a cell additive in electrolytic aluminium production, a catalyst in chemical reactors, an energy source in batteries, and a sanitising agent for swimming pools and hot tubs, as well as in specialised glass and ceramics [1]. Unfortunately, the widespread use of Li in industry and consumer markets since the 1990s has led to significant environmental pollution from Li waste. ...
Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes’ size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.
... Both sides play an essential and widespread role in society. 1,2 Within the organo-alkali metal complexes, and organometallic complexes in general, alkyllithium compounds dominate, being some of the most widely used reagents in both academia and industry. 1,3,4 First synthesised in 1917 by Wilhelm Schlenk, 5 they are reagents that at a first glance may appear simple and predictable, however on further investigation quickly reveal a much more complicated picture. ...
... 1,2 Within the organo-alkali metal complexes, and organometallic complexes in general, alkyllithium compounds dominate, being some of the most widely used reagents in both academia and industry. 1,3,4 First synthesised in 1917 by Wilhelm Schlenk, 5 they are reagents that at a first glance may appear simple and predictable, however on further investigation quickly reveal a much more complicated picture. ...
... From a bonding perspective, the M-C bond gets more polar (can be superficially understood as the metals' electronegativity gets smaller) and ionic and hence, more reactive. 1,9,10 The steric and electronic properties of the carbanion substituent affects the level of aggregation as well. Electron donating groups destabilise the carbanion, whereas electron withdrawing groups help to stabilise it. ...
Organo-alkali metal reagents are essential tools in synthetic chemistry. Alkali metal organometallics aggregate in solution and solid-state forming clusters and polymers. The structure of these aggregates and their structure-reactivity relationship have been of great interest for many decades. This Perspective will look at the strategies that have been employed to isolate low aggregates and, in particular, monomeric complexes of the most common alkali metal alkyls (M = Li-Cs, R = methyl, trimethylsilylmethyl, bis/tris(trimethylsilylmethyl), butyls and benzyl) and the relationship between level of aggregation, structure and reactivity.
... Their relative ease of synthesis combined with high Brønsted basicity and solubility in common organic solvents has held organolithium reagents as the gold standard within polar organometallic chemistry for over 100 years, so much so the key reagents are commercially available. [1,2] One of their main synthetic applications is their effectiveness in deprotonative metalation (or lithiation) reactions of aromatic and benzylic substrates, which transforms relatively inert CÀ H bonds into more reactive CÀ Li bonds ( Figure 1a). Recently, the World has witnessed a groundswell of interest in the need for sustainability and chemistry is no exception, with organometallic chemists now looking beyond lithium for alternatives, due to its spiralling cost and potential instability of supply chains. ...
... [56,57] We were also interested in the solution state of our metalated intermediates as that would give us a better indication of the aggregation of the sodiated intermediates in our model reaction. 1 H DOSY NMR of the crystals of polymeric 2 b in C 6 D 6 revealed a surprising degree of disaggregation, with a calculated MW of 426 g mol À 1 . This experimental molecular weight could indicate an equilibrium between a monomer (301 g mol À 1 ) and dimer (602 g mol À 1 ) which lies closer to the monomer or alternatively could be a C 6 D 6 solvated monomer (379 g mol À 1 ) . 1 H DOSY NMR of 2 c in C 6 D 6 also displayed a high level of disaggregation, the calculated MW of 314 g mol À 1 giving a strong indication that the metalated species adopts a monomeric structure in C 6 D 6 . ...
... This experimental molecular weight could indicate an equilibrium between a monomer (301 g mol À 1 ) and dimer (602 g mol À 1 ) which lies closer to the monomer or alternatively could be a C 6 D 6 solvated monomer (379 g mol À 1 ) . 1 H DOSY NMR of 2 c in C 6 D 6 also displayed a high level of disaggregation, the calculated MW of 314 g mol À 1 giving a strong indication that the metalated species adopts a monomeric structure in C 6 D 6 . Unsurprisingly, the solution state structure of 2 d in C 6 D 6 was suggested to be monomeric (339 g mol À 1 ) retaining its discrete structure from the solid-state. ...
Deaggregating the alkyl sodium NaCH2SiMe3 with polydentate nitrogen ligands enables the preparation and characterisation of new, hydrocarbon soluble chelated alkylsodium reagents. Equipped with significantly enhanced metalating power over their organolithium counterparts, these systems can promote controlled sodiation of weakly acidic benzylic C−H bonds from a series of toluene derivatives under mild stoichiometric conditions. This has been demonstrated through the benzylic aroylation of toluenes with Weinreb amides, that delivers a wide range of 2‐arylacetophenones in good to excellent yields. Success in isolating and determining the structures of key organometallic intermediates has provided useful mechanistic insight into these new sodium‐mediated transformations.
... This required specialist apparatus, which was detailed and illustrated in Schlenk's original manuscript, to perform sensitive filtrations with the strict exclusion of air. 2 Showcasing the immense utility of these early technical developments, Schlenk went on to discover organolithium compounds such as MeLi and PhLi in 1917, 3 reagents that are now ubiquitous in synthetic chemistry with extensive applications in industry and academic research. 4 Schlenk lines and related apparatus are now commonplace in many synthetic chemistry laboratories, since they allow the safe manipulation of air-and moisture-sensitive species, which in turn grants access to new compounds with unprecedented structures, bonding, reactivities and properties. While the underlying basis of Schlenk techniques has not changed significantly in 100 years, there has been a constant improvement in the methodologies as well as the availability of both routine and specialized equipment. ...
... [1,2] Moreover, both academia and industry draw upon the versatility and efficiency of these universal reagents which can act as nucleophiles, basic ("deprotonating") [3] and reducing agents, [4] but also as polymerization initiators (elastomer sector). [5] Over 100 years ago in 1917, [6][7][8][9] Wilhelm Schlenk and Johanna Holtz reported on their seminal work "Über die einfachsten metallorganischen Verbindungen" comprising a series of organosodium compounds but also methyllithium, ethyllithium, n-propyllithium, and phenyllithium. Astoundingly, methyllithium featuring the simplest organometallic compound, and as such the most illustrious one, has never been obtained as a pure compound. ...
Commercially available stock solutions of organolithium reagents are well‐implemented tools in organic and organometallic chemistry. However, such solutions are inherently contaminated with lithium halide salts, which can complicate certain synthesis protocols and purification processes. Here, we report the isolation of chloride‐free methyllithium employing K[N(SiMe3)2] as a halide‐trapping reagent. The influence of distinct LiCl contaminations on the ⁷Li‐NMR chemical shift is examined and their quantification demonstrated. The structural parameters of new chloride‐free monomeric methyllithium complex [(Me3TACN)LiCH3], ligated by an azacrown ether, are assessed by comparison with a halide‐contaminated variant and monomeric lithium chloride [(Me3TACN)LiCl], further emphasizing the effect of halide impurities.
... [1,2] Weiterhin werden diese allgegenwärtigen Reagenzien in der akademischen Forschung als auch in der chemischen Industrie aufgrund ihrer Vielseitigkeit und Effizienz häufig genutzt. Sie reagieren als Nukleophile, Basen (Deprotonierungsagentien), [3] Reduktionsmittel, [4] als auch im Bereich der Elastomerensynthese als Polymerisationsstarter. [5] Vor mehr als 100 Jahren, [6][7][8][9] berichteten Wilhelm Schlenk und Johanna Holtz in ihren bahnbrechenden Arbeiten "Über die einfachsten metallorganischen Verbindungen", die eine Reihe von Organonatriumverbindungen, jedoch auch Methyllithium, Ethyllithium, n-Propyllithium und Phenyllithium umfassten. Erstaunlicherweise wurde Methyllithium, die einfachste und schillernste metallorganische Lithiumverbindung, bisher noch nie als Reinprodukt isoliert. ...
Commercially available stock solutions of organolithium reagents are well‐implemented tools in organic and organometallic chemistry. However, such solutions are “inherently” contaminated with lithium halide salts, which can complicate certain synthesis protocols and purification processes. Here, we report the synthesis and isolation of chloride‐free methyllithium employing K[N(SiMe3)2] as a halide‐trapping reagent. The influence of distinct LiCl contaminations on the 7Li NMR chemical shift is examined and their quantification demonstrated. The structural parameters of new chloride‐free monomeric methyllithium complex [(Me3TACN)LiCH3], ligated by an azacrown ether, are assessed by comparison with a halide‐contaminated variant and monomeric lithium chloride [(Me3TACN)LiCl], further emphasizing the effect of halide impurities.
... [19][20][21][22][23] The widespread application of organolithium reagents can be ascribed to their innate ability to predictably transform organic substrates into organolithium compounds, priming them to be further functionalized. 24 Throughout the evolution of these lithiation-substitution sequences, the generality and applicability of this approach has been well demonstrated for substrates that incorporate Lewis basic (directing) or anion stabilizing subunits. 25 For example, ortho-lithiations in aromatic systems not only emerged as the go to method for substitution reactions but also played a major role in the advancement of NMR techniques for organometallic structure determinations. ...
The selective functionalization of saturated oxygen heterocycles at positions remote to the embedded heteroatoms remains an outstanding challenge in organic synthesis. Although many methods exist for the undirected replacement of C–H bonds with heteroatomic subunits the number of site selective C–H functionalization reactions for the introduction of carbon-carbon bonds pales in comparison. This paper describes the initial stages of a long-term program aimed at elucidating how organolithium reagents can be re-engineered to selectively deprotonate and functionalize saturated heterocycles at new locations. Through rigorous NMR spectroscopic investigations, it was determined for the first time that the addition of Lewis basic phosphoramides can shift the equilibrium of strong organolithium bases, such as t-BuLi, to include the triple ion pair (t-Bu–Li–t-Bu) / L4Li which serves as a reservoir for the highly reactive separated ion pair t-Bu / L4Li . Because the Li-atom’s valences are saturated the Lewis acidity is significantly decreased and the basicity is maximized which allowed for the typical directing effects within oxygen heterocycles to be overridden and for remote sp3-CH bonds to be deprotonated. In certain cases, this enabled the removal of stronger C–H bonds in the presence of weaker C–H bonds. Furthermore, these newly accessed lithium aggregation states were leveraged to develop a simple γ-lithiation and capture protocol (lithium nucleophilic coupling – “LiNC”) of chromane heterocycles with a variety of alkyl halide electrophiles in good yields.
... Coordination complexes of alkali and alkaline earth metals have widespread applications in synthetic chemistry. [1][2][3][4][5][6][7][8][9][10][11][12] They are common ligand-transfer reagents for synthesis of a wide range of main-group, transition metal and f-block element complexes. They exhibit diversified structures with various degrees of aggregation. ...
... Hz, 1H, CH), 2.78-2.88 (m, 2H, CHMe 2 ), 3.54 (s, 24H, 18-crown-6), 6.14 (d, 3 J HÀ H = 8.0 Hz, 1H, Quinolyl), 6.19 (t, 3 J HÀ H = 8.0 Hz, 1H, Quinolyl), 6.56 (d, 3 J HÀ H = 8.0 Hz, 1H, Quinolyl) 6.67-6.78 ...
A series of alkali and alkaline earth metal complexes, and an ytterbium(II) complex of monoanionic [CH(ⁱPr2P−BH3)(C9H6N‐2)]⁻ ligand (abbreviated as LQPB⁻) were synthesized. Lithium complexes [Li(LQPB)(TMEDA)] (2, TMEDA=Me2NCH2CH2NMe2) and [Li(LQPB)(12‐crown‐4)] (3) were prepared by lithiation of 1 with LiⁿBu in the presence of TMEDA and 12‐crown‐4 ether, respectively. Treatment of 2 with NaOtBu and KOtBu, respectively, followed by addition of 18‐crown‐6 ether yielded monomeric sodium complex [Na(LQPB)(18‐crown‐6)] (4) and polymeric potassium derivative [K(LQPB)(18‐crown‐6)]n (5). Metalation of 1 with MgⁿBu2/TMEDA afforded [Mg(LQPB)2(TMEDA)] (6). Heavier group 2 complexes [Ca(LQPB)2(DME)2] (7), [Sr(LQPB)2]2 (8) and [Ba(LQPB)2(DME)] (9) were synthesized by metalation of 1 with the corresponding alkaline earth metal amide M[N(SiMe3)2]2(DME)n (M=Ca or Ba, n=2; M=Sr, n=0) in toluene under reflux conditions. Treatment of YbI2(THF)2 with potassium complex 5 led to isolation of mononuclear Yb(II) complex [Yb(LQPB)2(18‐crown‐6)] (10).
... [9] However, strictly controlled experimental conditions (low temperature, dry ethereal solvents, and inert atmosphere) are typically required to avoid undesired degradation pathways or side reactions. [10] The development of new sustainable protocols which enable the use of aerobic/protic conditions in alkali-metal-mediated transformations has profoundly reshaped the conceptual chemistry of these highly polar organometallic reagents. [11] In this context, we recently reported that alkyllithiums can efficiently promote either chemo-and regioselective DoM, [12] benzylic metalation [13] and nucleophilic acyl substitution (S N Ac) [14] reactions using both deep eutectic solvents (DESs) and cyclopentyl methyl ether (CPME) [15] as sustainable reaction media, working at room temperature, under air/moisture. ...
A straightforward and efficient protocol to promote the metalation/anionic Fries rearrangements of O‐aryl carbamates, using for the first time a lithium amide as metalating agent under aerobic/ambient‐friendly reaction conditions, is reported. This approach enables the sustainable preparation of salicylamide derivatives with high levels of chemoselectivity within ultrafast reaction times, working at room temperature in the presence of air/moisture, and using environmentally responsible cyclopentyl methyl ether as a solvent. Furthermore, the regioselective manipulation of O‐2‐tolyl carbamates has been accomplished using interchangeably alkyllithiums or lithium amides, with an unexpected beneficial contribution from the employment of biorenewable protic eutectic mixtures as non‐innocent reaction media.
