An NMR Spectroscopy View on London Dispersion in Catalysis: Detection, Quantification, and Application in Ion Pair and Transition Metal Catalysis.

ConspectusThe energetic contribution of London dispersion (LD) can cover a broad range from very few to hundreds of kJ mol-1 for extended interaction interfaces due to its pairwise additivity. However, for a designed and successful application of LD in chemical catalysis, there are still many obstacles and questions that remain. In principle, LD can be regarded as the attractive part of the van der Waals potential. Thus, considering the whole van der Waals potential, including the repulsive part (steric repulsion), the ideal solution to the problem in catalysis would be to design compatible interaction interfaces at exactly the correct distance. In the case of a self-assembled, flexible structure arrangement, entropic contributions and solvent interactions might be detrimental. In the case of a rigid catalyst pocket, steric hindrance might not allow for large substituents that are usually applied as dispersion energy donors (DEDs). For a working catalytic system, the following question arises: how is it possible to dissect the complex interaction interfaces in terms of energetic contributions? Usually, the energetic contribution of LD to catalysis is addressed by using calculations. However, adequately computing the correct energetic contributions can be extremely challenging for a vast conformational space with all kinds of intermolecular interactions. Thus, experimental data are essential for comparison or benchmarking.Therefore, in this Account, we describe our quest for detailed experimental data obtained via NMR spectroscopy to experimentally dissect and quantify LD in catalytic systems. In addition, we address the question of whether bulky substituents used as DEDs can be used in confined catalytic pockets. With the example of Pd phosphoramidite complexes, we show how it is possible to experimentally dissect and quantify the contribution of individual interaction areas in complicated transition metal complexes. Furthermore, a correlation between conformational rigidity and heterodimer preference clearly reveals that LD can only unfold its full potential in cases where entropic contributions are minimized. This finding can also explain the small contribution of LD in flexible and solvent-exposed molecular balances. In the field of Brønsted acid catalysis, we demonstrated that LD has a strong influence on the structures, stability, and populations of confined catalytic intermediates. LD is key for populating higher aggregates such as dimers. In addition, offsets between the experimental and computational results were observed and attributed to solvent-solute dispersion interactions. We studied the delicate interplay of attractive and repulsive interactions by adding bulky DED substituents onto a substrate, which can function as a molecular balance system. Intriguingly, the effect of LD on the free substrate was straightforwardly transferred onto the highly confined intermediates. Furthermore, this effect could even be read out in the enantioselectivities of the underlying reaction. This conceptualized a general approach regarding how LD can be used beneficially in catalysis to convert from moderate/good to excellent stereoselectivities. It showcased that bulky groups such as tert-butyl must not only be regarded as occupied volumes.

Chiral Diselenophosphoric Acids for Ion Pair Catalysis: A Novel Approach to Enhance Both Proton Donating and Proton Accepting Properties.

The activation of poorly reactive substrates via strong chiral acids is a central topic in asymmetric ion pair catalysis these days. Despite highly successful scaffolds such as N-triflylphosphoramides, these catalysts either lack C2-symmetry or provide multiple H-bond acceptor sites, leading to lower ee values for certain reactions. We present BINOL-based diselenophosphoric acids (DSA) as an extremely promising alternative. Using an intertwined approach of synthesis and NMR studies, we developed a synthetic approach to DSA with up to 98 % NMR yield. The obtained acids provide both very high proton donor and proton acceptor properties, a bifunctionality, which is key to catalytic applications. Indeed, first reactivity test proved the much higher acidity of DSA and its ability to initiate Mukaiyama-Mannich reaction and protodesilylation of silyl ethers. Together with their C2-symmetry, the single donor and single acceptor situation, the decreased tendency of self-association, and the straightforward synthesis with potential 3,3'-substitution, the DSA provide all features ideal for the further development of ion pair catalysis.

Azotriptycenes: Photoswitchable Molecular Brakes.

The control of molecular motions is a central topic of molecular machine research. Molecular brakes are fundamental building blocks towards such goal as they allow deliberately decelerating specific motions after an outside stimulus is applied. Here we present azotriptycenes as structural framework for light-controlled molecular brakes. The intrinsic kinetics and their changes upon azotriptycene isomerization are scrutinized comprehensively by a mixed theoretical and variable temperature NMR approach. With azotriptycenes C-N bond rotation rates can be decelerated or accelerated reversibly by up to five orders of magnitude. Rate change effects are highly localized and are strongest for the C-N bond connecting a triptycene rotor fragment to the central diazo group. The detailed mechanistic insights provide a solid basis for further conscious design and applications in the future.

Liquid Ammonia: More than an Innocent Solvent for Zintl Anions.

Liquid ammonia as the original solvent for Zintl anions has been replaced by easier to handle or more versatile solvents in most recent Zintl chemistry. However, methodological advances have made it possible to structurally investigate the anions in ammoniate crystals via crystallography or in the solutions themselves via nuclear magnetic resonance. While in some cases liquid ammonia acts as an innocent solvent, it also provides different possibilities of direct involvement in chemical reactions. In addition to simple dissolution without changes to the anions observed in the solid starting materials, protonation of the anion, incongruent dissolution involving redox processes, and further oxidation and reduction products have been observed. The use of the solvent liquid ammonia under ambient pressure is limited to low temperatures, which in turn allows the monitoring of kinetically stabilized species, some of which cannot be accessed at higher temperatures. In this work, the available literature reports are summarized or referenced, and compounds that have been characterized as new ammoniate crystals are presented and contextualized. Innocent dissolution is observed for clusters involved in K2.9Rb5.1[Si4][Si9]·15NH3, Cs4Sn9·12NH3, Cs4Pb9·5NH3, and [Rb@[18]crown-6]2[Rb@[2.2.2]crypt]Rb[Ge9]·4NH3. Formal protonation of [Ge4]4- results in the crystallization of [Na@[2.2.2]crypt]2[H2Ge4]·3NH3. Tt52- (Tt = Sn or Pb) and HSi93- cannot be accessed in a binary solid state material but can be crystallized in co-crystals of PPh3 in [Rb@[2.2.2]crypt]2[Sn5][PPh3]2·NH3, [Rb@[2.2.2]crypt]2[Pb5][PPh3]2·NH3, and [K@[2.2.2]crypt]3[HSi9][PPh3]·5NH3.

Unravelling White Phosphorus: Experimental and Computational Studies Reveal the Mechanisms of P4 Hydrostannylation.

The hydrostannylation of white phosphorus (P4) allows this crucial industrial precursor to be easily transformed into useful P1 products via direct, 'one pot' (or even catalytic) procedures. However, a thorough mechanistic understanding of this transformation has remained elusive, hindering attempts to use this rare example of successful, direct P4 functionalization as a model for further reaction development. Here, we provide a deep and generalizable mechanistic picture for P4 hydrostannylation by combining DFT calculations with in situ31P NMR reaction monitoring and kinetic trapping of previously unobservable reaction intermediates using bulky tin hydrides. The results offer important insights into both how this reaction proceeds and why it is successful and provide implicit guidelines for future research in the field of P4 activation.

Reactivity of Superbasic Carbanions Generated via Reductive Radical-Polar Crossover in the Context of Photoredox Catalysis.

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

Brønsted Acid Catalysis-Controlling the Competition between Monomeric versus Dimeric Reaction Pathways Enhances Stereoselectivities.

Chiral phosphoric acids (CPA) have become a privileged catalyst type in organocatalysis, but the selection of the optimum catalyst is still challenging. So far hidden competing reaction pathways may limit the maximum stereoselectivities and the potential of prediction models. In CPA-catalyzed transfer hydrogenation of imines, we identified for many systems two reaction pathways with inverse stereoselectivity, featuring as active catalyst either one CPA or a hydrogen bond bridged dimer. NMR measurements and DFT calculations revealed the dimeric intermediate and a stronger substrate activation via cooperativity. Both pathways are separable: Low temperatures and high catalysts loadings favor the dimeric pathway (ee up to -98 %), while low temperatures with reduced catalyst loading favor the monomeric pathway and give significantly enhanced ee (92-99 % ee; prior 68-86 % at higher temperatures). Thus, a broad impact is expected on CPA catalysis regarding reaction optimization and prediction.

Enforced Electronic-Donor-Acceptor Complex Formation in Water for Photochemical Cross-Coupling.

The amino alcohol meglumine solubilizes organic compounds in water and enforces the formation of electron donor acceptor (EDA) complexes of haloarenes with indoles, anilines, anisoles or thiols, which are not observed in organic solvents. UV-A photoinduced electron transfer within the EDA complexes induces the mesolytic cleavage of the halide ion and radical recombination of the arenes leading, after rearomatization and proton loss to C-C or C-S coupling products. Depending on the substitution pattern selective and unique cross-couplings are observed. UV and NMR measurements reveal the importance of the assembly for the photoinduced reaction. Enforced EDA aggregate formation in water allows new activation modes for organic photochemical synthesis.

Tilting the Balance: London Dispersion Systematically Enhances Enantioselectivities in Brønsted Acid Catalyzed Transfer Hydrogenation of Imines.

London dispersion (LD) is attracting more and more attention in catalysis since LD is ubiquitously present and cumulative. Since dispersion is hard to grasp, recent research has concentrated mainly on the effect of LD in individual catalytic complexes or on the impact of dispersion energy donors (DEDs) on balance systems. The systematic transfer of LD effects onto confined and more complex systems in catalysis is still in its infancy, and no general approach for using DED residues in catalysis has emerged so far. Thus, on the example of asymmetric Brønsted acid catalyzed transfer hydrogenation of imines, we translated the findings of previously isolated balance systems onto confined catalytic intermediates, resulting in a systematic enhancement of stereoselectivity when employing DED-substituted substrates. As the imine substrate is present as Z- and E-isomers, which can, respectively, be converted to R- and S-product enantiomers, implementing tert-butyl groups as DED residues led to an additional stabilization of the Z-imine by up to 4.5 kJ/mol. NMR studies revealed that this effect is transferred onto catalyst/imine and catalyst/imine/nucleophile intermediates and that the underlying reaction mechanism is not affected. A clear correlation between ee and LD stabilization was demonstrated for 3 substrates and 10 catalysts, allowing to convert moderate-good to good-excellent enantioselectivities. Our findings conceptualize a general approach on how to beneficially employ DED residues in catalysis: they clearly showcase that bulky alkyl residues such as tert-butyl groups must be considered regarding not only their repulsive steric bulk but also their attractive properties even in catalytic complexes.

Deeper Insight into Photopolymerization: The Synergy of Time-Resolved Nonuniform Sampling and Diffusion NMR.

The comprehensive real-time in situ monitoring of chemical processes is a crucial requirement for the in-depth understanding of these processes. This monitoring facilitates an efficient design of chemicals and materials with the precise properties that are desired. This work presents the simultaneous utilization and synergy of two novel time-resolved NMR methods, i.e., time-resolved diffusion NMR and time-resolved nonuniform sampling. The first method allows the average diffusion coefficient of the products to be followed, while the second method enables the particular products to be monitored. Additionally, the average mass of the system is calculated with excellent resolution using both techniques. Employing both methods at the same time and comparing their results leads to the unequivocal validation of the assignment in the second method. Importantly, such validation is possible only via the simultaneous combination of both approaches. While the presented methodology was utilized for photopolymerization, it can also be employed for any other polymerization process, complexation, or, in general, chemical reactions in which the evolution of mass in time is of importance.

Transition-Metal-Stabilized Heavy Tetraphospholide Anions.

Phosphorus analogues of the ubiquitous cyclopentadienyl (Cp) are a rich and diverse family of compounds, which have found widespread use as ligands in organometallic complexes. By contrast, phospholes incorporating heavier group 14 elements (Si, Ge, Sn, and Pb) are hardly known. Here, we demonstrate the isolation of the first metal complexes featuring heavy cyclopentadienyl anions SnP42- and PbP42-. The complexes [(η4-tBu2C2P2)2Co2(µ,η5:η5-P4Tt)] [Tt = Sn (6), Pb (7)] are formed by reaction of white phosphorus (P4) with cyclooctadiene cobalt complexes [Ar'TtCo(η4-P2C2tBu2)(η4-COD)] [Tt = Sn (2), Pb (3), Ar' = C6H3-2,6{C6H3-2,6-iPr2}2, COD = cycloocta-1,5-diene] and Tt{Co(η4-P2C2tBu2)(COD)}2 [Tt = Sn (4), Pb (5)]. While the SnP42- complex 6 was isolated as a pure and stable compound, compound 7 eliminated Pb(0) below room temperature to afford [(η4-tBu2C2P2)2Co2(µ,η4:η4-P4) (8), which is a rare example of a tripledecker complex with a P42- middle deck. The electronic structures of 6-8 are analyzed using theoretical methods including an analysis of intrinsic bond orbitals and magnetic response theory. Thereby, the aromatic nature of P5- and SnP42- was confirmed, while for P42-, a specific type of symmetry-induced weak paramagnetism was found that is distinct from conventional antiaromatic species.

Hydrogen-Bond-Modulated Nucleofugality of SeIII Species to Enable Photoredox-Catalytic Semipinacol Manifolds.

Chemical bond activations mediated by H-bond interactions involving highly electronegative elements such as nitrogen and oxygen are powerful tactics in modern catalysis research. On the contrary, kindred catalytic regimes in which heavier, less electronegative elements such as selenium engage in H-bond interactions to co-activate C-Se σ-bonds under oxidative conditions are elusive. Traditional strategies to enhance the nucleofugality of selenium residues predicate on the oxidative addition of electrophiles onto SeII -centers, which entails the elimination of the resulting SeIV moieties. Catalytic procedures in which SeIV nucleofuges are substituted rather than eliminated are very rare and, so far, not applicable to carbon-carbon bond formations. In this study, we introduce an unprecedented combination of O-H⋅⋅⋅Se H-bond interactions and single electron oxidation to catalytically generate SeIII nucleofuges that allow for the formation of new C-C σ-bonds by means of a type I semipinacol process in high yields and excellent selectivity.

Extended Hydrogen Bond Networks for Effective Proton-Coupled Electron Transfer (PCET) Reactions: The Unexpected Role of Thiophenol and Its Acidic Channel in Photocatalytic Hydroamidations.

Preorganization and aggregation in photoredox catalysis can significantly affect reactivities or selectivities but are often neglected in synthetic and mechanistic studies, since the averaging effect of flexible ensembles can effectively hide the key activation signatures. In addition, aggregation effects are often overlooked due to highly diluted samples used in many UV studies. One prominent example is Knowles's acceleration effect of thiophenol in proton-coupled electron transfer mediated hydroamidations, for which mainly radical properties were discussed. Here, cooperative reactivity enhancements of thiophenol/disulfide mixtures reveal the importance of H-bond networks. For the first time an in-depth NMR spectroscopic aggregation and H-bond analysis of donor and acceptor combined with MD simulations was performed revealing that thiophenol acts also as an acid. The formed phosphate-H+-phosphate dimers provide an extended H-bond network with amides allowing a productive regeneration of the photocatalyst to become effective. The radical and acidic properties of PhSH were substituted by Ph2S2 and phosphoric acid. This provides a handle for optimization of radical and ionic channels and yields accelerations up to 1 order of magnitude under synthetic conditions. Reaction profiles with different light intensities unveil photogenerated amidyl radical reservoirs lasting over minutes, substantiating the positive effect of the H-bond network prior to radical cyclization. We expect the presented concepts of effective activation via H-bond networks and the reactivity improvement via the separation of ionic and radical channels to be generally applicable in photoredox catalysis. In addition, this study shows that control of aggregates and ensembles will be a key to future photocatalysis.

Enantioselective [2 + 2] Photocycloaddition via Iminium Ions: Catalysis by a Sensitizing Chiral Brønsted Acid.

N,O-Acetals derived from α,ß-unsaturated ß-aryl substituted aldehydes and (1-aminocyclohexyl)methanol were found to undergo a catalytic enantioselective [2 + 2] photocycloaddition to a variety of olefins (19 examples, 54-96% yield, 84-98% ee). The reaction was performed by visible light irradiation (λ = 459 nm). A chiral phosphoric acid (10 mol %) with an (R)-1,1'-bi-2-naphthol (binol) backbone served as the catalyst. The acid displays two thioxanthone groups attached to position 3 and 3' of the binol core via a meta-substituted phenyl linker. NMR studies confirmed the formation of an iminium ion which is attached to the acid counterion in a hydrogen-bond assisted ion pair. The catalytic activity of the acid rests on the presence of the thioxanthone moieties which enable a facile triplet energy transfer and an efficient enantioface differentiation.

A Structural Diversity of Molecular Alkaline-Earth-Metal Polyphosphides: From Supramolecular Wheel to Zintl Ion.

A series of molecular group 2 polyphosphides has been synthesized by using air-stable [Cp*Fe(η5 -P5 )] (Cp*=C5 Me5 ) or white phosphorus as polyphosphorus precursors. Different types of group 2 reagents such as organo-magnesium, mono-valent magnesium, and molecular calcium hydride complexes have been investigated to activate these polyphosphorus sources. The organo-magnesium complex [(Dipp BDI-Mg(CH3 ))2 ] (Dipp BDI={[2,6-i Pr2 C6 H3 NCMe]2 CH}- ) reacts with [Cp*Fe(η5 -P5 )] to give an unprecedented Mg/Fe-supramolecular wheel. Kinetically controlled activation of [Cp*Fe(η5 -P5 )] by different mono-valent magnesium complexes allowed the isolation of Mg-coordinated formally mono- and di-reduced products of [Cp*Fe(η5 -P5 )]. To obtain the first examples of molecular calcium-polyphosphides, a molecular calcium hydride complex was used to reduce the aromatic cyclo-P5 ring of [Cp*Fe(η5 -P5 )]. The Ca-Fe-polyphosphide is also characterized by quantum chemical calculations and compared with the corresponding Mg complex. Moreover, a calcium coordinated Zintl ion (P7 )3- was obtained by molecular calcium hydride mediated P4 reduction.

Mixed Organometallic-Organic Hybrid Assemblies Based on the Diarsene Complex [Cp2 Mo2 (CO)4 (µ,η2 -As2 )], AgI Salts and N-Donor Organic Molecules.

The reaction of the organometallic diarsene complex [Cp2 Mo2 (CO)4 (η2 -As2 )] (1) with Ag[Al{OC(CF3 )3 }4 ] (Ag[TEF]) yielded the AgI monomer [Ag(η2 -1)3 ][TEF] (2). This compound exhibits dynamic behavior in solution, which allows directed selective synthesis of unprecedented organometallic-organic hybrid assemblies upon its reaction with N-donor organic molecules by a stepwise pathway, which is supported by DFT calculations. Accordingly, the reaction of 2 with 2,2'-bipyrimidine (L1) yielded the dicationic molecular compound [{(η2 -1)2 Ag}2 (µ-L1)][TEF]2 (3) or the 1D polymer [{(η2 -1)Ag}(µ-L1)]n [TEF]n (4) depending on the ratio of the reactants. However, its reactions with the pyridine-based linkers 4,4'-bipyridine (L2), 1,2-bis(4-pyridyl)ethylene (L3) and 1,2-bis(4-pyridyl)ethyne (L4) allowed the formation of the 2D polymers [{(η2 -1)Ag}2 (µ-Lx)3 ]n [TEF]2n [Lx=L2 (5), L3 (6), L4 (7), respectively]. Additionally, this concept was extended to step-by-step one-pot reactions of 1, [Ag(CH3 CN)3 ][Al{OC(CF3 )2 (CCl3 )}4 ] ([Ag(CH3 CN)3 ][TEFCl ]) and linkers L2-L4 to produce the 2D polymers [{(η2 -1)Ag}2 (µ,Lx)3 ]n [TEFCl ]2n [Lx=L2 (8), L3 (9), L4 (10), respectively].

Insights Into the Micelle-Induced ß-Hairpin-to-α-Helix Transition of a LytA-Derived Peptide by Photo-CIDNP Spectroscopy.

A choline-binding module from pneumococcal LytA autolysin, LytA239-252, was reported to have a highly stable nativelike ß-hairpin in aqueous solution, which turns into a stable amphipathic α-helix in the presence of micelles. Here, we aim to obtain insights into this DPC-micelle triggered ß-hairpin-to-α-helix conformational transition using photo-CIDNP NMR experiments. Our results illustrate the dependency between photo-CIDNP phenomena and the light intensity in the sample volume, showing that the use of smaller-diameter (2.5 mm) NMR tubes instead of the conventional 5 mm ones enables more efficient illumination for our laser-diode light setup. Photo-CIDNP experiments reveal different solvent accessibility for the two tyrosine residues, Y249 and Y250, the latter being less accessible to the solvent. The cross-polarization effects of these two tyrosine residues of LytA239-252 allow for deeper insights and evidence their different behavior, showing that the Y250 aromatic side chain is involved in a stronger interaction with DPC micelles than Y249 is. These results can be interpreted in terms of the DPC micelle disrupting the aromatic stacking between W241 and Y250 present in the nativelike ß-hairpin, hence initiating conversion towards the α-helix structure. Our photo-CIDNP methodology represents a powerful tool for observing residue-level information in switch peptides that is difficult to obtain by other spectroscopic techniques.

Noncovalent CH-π and π-π Interactions in Phosphoramidite Palladium(II) Complexes with Strong Conformational Preference.

The weak noncovalent interactions and flexibility of ligands play a key role in enantioselective metal-catalyzed reactions. In transition metal complexes and their catalytic applications, the experimental assessment and the design of key interactions is as difficult as the prediction of the enantioselectivities, especially for flexible, privileged ligands such as chiral phosphoramidites. Therefore, the interligand interactions in cis-PdII L2 Cl2 phosphoramidite complexes were investigated by NMR spectroscopy and computations. We were able to induce a strong conformational preference by breaking the symmetry of the C2 -symmetric side chain of one of the ligands, and shift the equilibrium between hetero- and homocomplexes towards heterocomplexes because of interligand interactions in the cis-complexes. The modulation of aryl substituents was exploited, along with the solvent effect. The combined CH-π and π-π interactions reveal design patterns for binding and folding of chiral ligands and catalysts.

Photocatalytic Arylation of P4 and PH3 : Reaction Development Through Mechanistic Insight.

Detailed 31 P{1 H} NMR spectroscopic investigations provide deeper insight into the complex, multi-step mechanisms involved in the recently reported photocatalytic arylation of white phosphorus (P4 ). Specifically, these studies have identified a number of previously unrecognized side products, which arise from an unexpected non-innocent behavior of the commonly employed terminal reductant Et3 N. The different rate of formation of these products explains discrepancies in the performance of the two most effective catalysts, [Ir(dtbbpy)(ppy)2 ][PF6 ] (dtbbpy=4,4'-di-tert-butyl-2,2'-bipyridine) and 3DPAFIPN. Inspired by the observation of PH3 as a minor intermediate, we have developed the first catalytic procedure for the arylation of this key industrial compound. Similar to P4 arylation, this method affords valuable triarylphosphines or tetraarylphosphonium salts depending on the steric profile of the aryl substituents.

A Thioxanthone Sensitizer with a Chiral Phosphoric Acid Binding Site: Properties and Applications in Visible Light-Mediated Cycloadditions.

A chiral phosphoric acid with a 2,2'-binaphthol core was prepared that displays two thioxanthone moieties at the 3,3'-position as light-harvesting antennas. Despite its relatively low triplet energy, the phosphoric acid was found to be an efficient catalyst for the enantioselective intermolecular [2+2] photocycloaddition of ß-carboxyl-substituted cyclic enones (e.r. up to 93:7). Binding of the carboxylic acid to the sensitizer is suggested by NMR studies and by DFT calculations to occur by means of two hydrogen bonds. The binding event not only enables an enantioface differentiation but also modulates the triplet energy of the substrates.