Long-range electrostatic effects from intramolecular Lewis acid binding influence the redox properties of cobalt-porphyrin complexes.

A CoII-porphyrin complex (1) with an appended aza-crown ether for Lewis acid (LA) binding was synthesized and characterized. NMR spectroscopy and electrochemistry show that cationic group I and II LAs (i.e., Li+, Na+, K+, Ca2+, Sr2+, and Ba2+) bind to the aza-crown ether group of 1. The binding constant for Li+ is comparable to that observed for a free aza-crown ether. LA binding causes an anodic shift in the CoII/CoI couple of between 10 and 40 mV and also impacts the CoIII/CoII couple. The magnitude of the anodic shift of the CoII/CoI couple varies linearly with the strength of the LA as determined by the pKa of the corresponding metal-aqua complex, with dications giving larger shifts than monocations. The extent of the anodic shift of the CoII/CoI couple also increases as the ionic strength of the solution decreases. This is consistent with electric field effects being responsible for the changes in the redox properties of 1 upon LA binding and provides a novel method to tune the reduction potential. Density functional theory calculations indicate that the bound LA is 5.6 to 6.8 Å away from the CoII ion, demonstrating that long-range electrostatic effects, which do not involve changes to the primary coordination sphere, are responsible for the variations in redox chemistry. Compound 1 was investigated as a CO2 reduction electrocatalyst and shows high activity but rapid decomposition.

Effect of 6,6'-Substituents on Bipyridine-Ligated Ni Catalysts for Cross-Electrophile Coupling.

A family of 4,4'-tBu2-2,2'-bipyridine (tBubpy) ligands with substituents in either the 6-position, 4,4'-tBu2-6-Me-bpy (tBubpyMe), or 6 and 6'-positions, 4,4'-tBu2-6,6'-R2-bpy (tBubpyR2; R = Me, iPr, sBu, Ph, or Mes), was synthesized. These ligands were used to prepare Ni complexes in the 0, I, and II oxidation states. We observed that the substituents in the 6 and 6'-positions of the tBubpy ligand impact the properties of the Ni complexes. For example, bulkier substituents in the 6,6'-positions of tBubpy better stabilized (tBubpyR2)NiICl species and resulted in cleaner reduction from (tBubpyR2)NiIICl2. However, bulkier substituents hindered or prevented coordination of tBubpyR2 ligands to Ni0(cod)2. In addition, by using complexes of the type (tBubpyMe)NiCl2 and (tBubpyR2)NiCl2 as precatalysts for different XEC reactions, we demonstrated that the 6 or 6,6' substituents lead to major differences in catalytic performance. Specifically, while (tBubpyMe)NiIICl2 is one of the most active catalysts reported to date for XEC and can facilitate XEC reactions at room temperature, lower turnover frequencies were observed for catalysts containing tBubpyR2 ligands. A detailed study on the catalytic intermediates (tBubpy)Ni(Ar)I and (tBubpyMe2)Ni(Ar)I revealed several factors that likely contributed to the differences in catalytic activity. For example, whereas complexes of the type (tBubpy)Ni(Ar)I are low spin and relatively stable, complexes of the type (tBubpyMe2)Ni(Ar)I are high-spin and less stable. Further, (tBubpyMe2)Ni(Ar)I captures primary and benzylic alkyl radicals more slowly than (tBubpy)Ni(Ar)I, consistent with the lower activity of the former in catalysis. Our findings will assist in the design of tailor-made ligands for Ni-catalyzed transformations.

Photoelectrochemical CO2 Reduction to CO Enabled by a Molecular Catalyst Attached to High-Surface-Area Porous Silicon.

A high-surface-area p-type porous Si photocathode containing a covalently immobilized molecular Re catalyst is highly selective for the photoelectrochemical conversion of CO2 to CO. It gives Faradaic efficiencies of up to 90% for CO at potentials of -1.7 V (versus ferrocenium/ferrocene) under 1 sun illumination in an acetonitrile solution containing phenol. The photovoltage is approximately 300 mV based on comparisons with similar n-type porous Si cathodes in the dark. Using an estimate of the equilibrium potential for CO2 reduction to CO under optimized reaction conditions, photoelectrolysis was performed at a small overpotential, and the onset of electrocatalysis in cyclic voltammograms occurred at a modest underpotential. The porous Si photoelectrode is more stable and selective for CO production than the photoelectrode generated by attaching the same Re catalyst to a planar Si wafer. Further, facile characterization of the porous Si-based photoelectrodes using transmission mode FTIR spectroscopy leads to highly reproducible catalytic performance.

Bulky, electron-rich, renewable: analogues of Beller's phosphine for cross-couplings.

In recent years, considerable progress has been made in the conversion of biomass into renewable chemicals, yet the range of value-added products that can be formed from biomass remains relatively small. Herein, we demonstrate that molecules available from biomass serve as viable starting materials for the synthesis of phosphine ligands, which can be used in homogeneous catalysis. Specifically, we prepared renewable analogues of Beller's ligand (di(1-adamantyl)-n-butylphosphine, cataCXium® A), which is widely used in homogeneous catalysis. Our new renewable phosphine ligands facilitate Pd-catalysed Suzuki-Miyaura, Stille, and Buchwald-Hartwig coupling reactions with high yields, and our catalytic results can be rationalized based on the stereoelectronic properties of the ligands. The new phosphine ligands generate catalytic systems that can be applied for the late-stage functionalization of commercial drugs.

Comparative study of CO2 insertion into pincer supported palladium alkyl and aryl complexes.

The insertion of CO2 into metal alkyl bonds is a crucial elementary step in transition metal-catalyzed processes for CO2 utilization. Here, we synthesize pincer-supported palladium complexes of the type (tBuPBP)Pd(alkyl) (tBuPBP = B(NCH2PtBu2)2C6H4-; alkyl = CH2CH3, CH2CH2CH3, CH2C6H5, and CH2-4-OMe-C6H4) and (tBuPBP)Pd(C6H5) and compare the rates of CO2 insertion into the palladium alkyl bonds to form metal carboxylate complexes. Although, the rate constant for CO2 insertion into (tBuPBP)Pd(CH2CH3) is more than double the rate constant we previously measured for insertion into the palladium methyl complex (tBuPBP)Pd(CH3), insertion into (tBuPBP)Pd(CH2CH2CH3) occurs approximately one order of magnitude slower than (tBuPBP)Pd(CH3). CO2 insertion into the benzyl complexes (tBuPBP)Pd(CH2C6H5) and (tBuPBP)Pd(CH2-4-OMe-C6H4) is significantly slower than any of the n-alkyl complexes, and CO2 does not insert into the palladium phenyl bond of (tBuPBP)Pd(C6H5). While (tBuPBP)Pd(CH2CH3) and (tBuPBP)Pd(CH2CH2CH3) are resistant to ß-hydride elimination, we were unable to synthesize complexes with n-butyl, iso-propyl, and tert-butyl ligands due to ß-hydride elimination and an unusual reductive coupling, which involves the formation of new C-B bonds. This reductive process also occurred for (tBuPBP)Pd(CH2C6H5) at elevated temperature and a related process involving the formation of a new H-B bond prevented the isolation of (tBuPBP)PdH. DFT calculations provide insight into the relative rates of CO2 insertion and indicate that steric factors are critical. Overall, this work is one of the first comparative studies of the rates of CO2 insertion into different metal alkyl bonds and provides fundamental information that may be important for the development of new catalysts for CO2 utilization.

Synthesis and Surface Attachment of Molecular Re(I) Complexes Supported by Functionalized Bipyridyl Ligands.

Eleven 2,2'-bipyridine (bpy) ligands functionalized with attachment groups for covalent immobilization on silicon surfaces were prepared. Five of the ligands feature silatrane functional groups for attachment to metal oxide coatings on the silicon surfaces, while six contain either alkene or alkyne functional groups for attachment to hydrogen-terminated silicon surfaces. The bpy ligands were coordinated to Re(CO)5Cl to form complexes of the type Re(bpy)(CO)3Cl, which are related to known catalysts for CO2 reduction. Six of the new complexes were characterized using X-ray crystallography. As proof of principle, four molecular Re complexes were immobilized on either a thin layer of TiO2 on silicon or hydrogen-terminated silicon. The surface-immobilized complexes were characterized using X-ray photoelectron spectroscopy, IR spectroscopy, and cyclic voltammetry (CV) in the dark and for one representative example in the light. The CO stretching frequencies of the attached complexes were similar to those of the pure molecular complexes, but the CVs were less analogous. For two of the complexes, comparison of the electrocatalytic CO2 reduction performance showed lower CO Faradaic efficiencies for the immobilized complexes than the same complex in solution under similar conditions. In particular, a complex containing a silatrane linked to bpy with an amide linker showed poor catalytic performance and control experiments suggest that amide linkers in conjugation with a redox-active ligand are not stable under highly reducing conditions and alkyl linkers are more stable. A conclusion of this work is that understanding the behavior of molecular Re catalysts attached to semiconducting silicon is more complicated than related complexes, which have previously been immobilized on metallic electrodes.

Correlating Thermodynamic and Kinetic Hydricities of Rhenium Hydrides.

The kinetics of hydride transfer from Re(Rbpy)(CO)3H (bpy = 4,4'-R-2,2'-bipyridine; R = OMe, tBu, Me, H, Br, COOMe, CF3) to CO2 and seven different cationic N-heterocycles were determined. Additionally, the thermodynamic hydricities of complexes of the type Re(Rbpy)(CO)3H were established primarily using computational methods. Linear free-energy relationships (LFERs) derived by correlating thermodynamic and kinetic hydricities indicate that, in general, the rate of hydride transfer increases as the thermodynamic driving force for the reaction increases. Kinetic isotope effects range from inverse for hydride transfer reactions with a small driving force to normal for reactions with a large driving force. Hammett analysis indicates that hydride transfer reactions with greater thermodynamic driving force are less sensitive to changes in the electronic properties of the metal hydride, presumably because there is less buildup of charge in the increasingly early transition state. Bronsted α values were obtained for a range of hydride transfer reactions and along with DFT calculations suggest the reactions are concerted, which enables the use of Marcus theory to analyze hydride transfer reactions involving transition metal hydrides. It is notable, however, that even slight perturbations in the steric properties of the Re hydride or the hydride acceptor result in large deviations in the predicted rate of hydride transfer based on thermodynamic driving forces. This indicates that thermodynamic considerations alone cannot be used to predict the rate of hydride transfer, which has implications for catalyst design.

Homogeneous Organic Electron Donors in Nickel-Catalyzed Reductive Transformations.

Many contemporary organic transformations, such as Ni-catalyzed cross-electrophile coupling (XEC), require a reductant. Typically, heterogeneous reductants, such as Zn0 or Mn0, are used as the electron source in these reactions. Although heterogeneous reductants are highly practical for preparative-scale batch reactions, they can lead to complications in performing reactions on process scale and are not easily compatible with modern applications, such as flow chemistry. In principle, homogeneous organic reductants can address some of the challenges associated with heterogeneous reductants and also provide greater control of the reductant strength, which can lead to new reactivity. Nevertheless, homogeneous organic reductants have rarely been used in XEC. In this Perspective, we summarize recent progress in the use of homogeneous organic electron donors in Ni-catalyzed XEC and related reactions, discuss potential synthetic and mechanistic benefits, describe the limitations that inhibit their implementation, and outline challenges that need to be solved in order for homogeneous organic reductants to be widely utilized in synthetic chemistry. Although our focus is on XEC, our discussion of the strengths and weaknesses of different methods for introducing electrons is general to other reductive transformations.

Compact Super Electron-Donor to Monolayer MoS2.

The surface functionalization of two-dimensional (2D) materials with organic electron donors (OEDs) is a powerful tool to modulate the electronic properties of the material. Here we report a novel molecular dopant, Me-OED, that demonstrates record-breaking molecular doping to MoS2, achieving a carrier density of 1.10 ± 0.37 × 1014 cm-2 at optimal functionalization conditions; the achieved carrier density is much higher than those by other OEDs such as benzyl viologen and an OED based on 4,4'-bipyridine. This impressive doping power is attributed to the compact size of Me-OED, which leads to high surface coverage on MoS2. To confirm, we study tBu-OED, which has an identical reduction potential to Me-OED but is significantly larger. Using field-effect transistor measurements and spectroscopic characterization, we estimate the doping powers of Me- and tBu-OED are 0.22-0.44 and 0.11 electrons per molecule, respectively, in good agreement with calculations. Our results demonstrate that the small size of Me-OED is critical to maximizing the surface coverage and molecular interactions with MoS2, enabling us to achieve unprecedented doping of MoS2.

Ligand and solvent effects on CO2 insertion into group 10 metal alkyl bonds.

The insertion of carbon dioxide into metal element σ-bonds is an important elementary step in many catalytic reactions for carbon dioxide valorization. Here, the insertion of carbon dioxide into a family of group 10 alkyl complexes of the type (RPBP)M(CH3) (RPBP = B(NCH2PR2)2C6H4 -; R = Cy or t Bu; M = Ni or Pd) to generate κ1-acetate complexes of the form (RPBP)M{OC(O)CH3} is investigated. This involved the preparation and characterization of a number of new complexes supported by the unusual RPBP ligand, which features a central boryl donor that exerts a strong trans-influence, and the identification of a new decomposition pathway that results in C-B bond formation. In contrast to other group 10 methyl complexes supported by pincer ligands, carbon dioxide insertion into (RPBP)M(CH3) is facile and occurs at room temperature because of the high trans-influence of the boryl donor. Given the mild conditions for carbon dioxide insertion, we perform a rare kinetic study on carbon dioxide insertion into a late-transition metal alkyl species using ( t BuPBP)Pd(CH3). These studies demonstrate that the Dimroth-Reichardt parameter for a solvent correlates with the rate of carbon dioxide insertion and that Lewis acids do not promote insertion. DFT calculations indicate that insertion into ( t BuPBP)M(CH3) (M = Ni or Pd) proceeds via an SE2 mechanism and we compare the reaction pathway for carbon dioxide insertion into group 10 methyl complexes with insertion into group 10 hydrides. Overall, this work provides fundamental insight that will be valuable for the development of improved and new catalysts for carbon dioxide utilization.

Control of Catalyst Isomers Using an N-Phenyl-Substituted RN(CH2CH2PiPr2)2 Pincer Ligand in CO2 Hydrogenation and Formic Acid Dehydrogenation.

A novel pincer ligand, iPrPNPhP [PhN(CH2CH2PiPr2)2], which is an analogue of the versatile MACHO ligand, iPrPNHP [HN(CH2CH2PiPr2)2], was synthesized and characterized. The ligand was coordinated to ruthenium, and a series of hydride-containing complexes were isolated and characterized by NMR and IR spectroscopies, as well as X-ray diffraction. Comparisons to previously published analogues ligated by iPrPNHP and iPrPNMeP [CH3N(CH2CH2PiPr2)2] illustrate that there are large changes in the coordination chemistry that occur when the nitrogen substituent of the pincer ligand is altered. For example, ruthenium hydrides supported by the iPrPNPhP ligand always form the syn isomer (where syn/anti refer to the relative orientation of the group on nitrogen and the hydride ligand on ruthenium), whereas complexes supported by iPrPNHP form the anti isomer and complexes supported by iPrPNMeP form a mixture of syn and anti isomers. We evaluated the impact of the nitrogen substituent of the pincer ligand in catalysis by comparing a series of iPrPNRP (R = H, Me, Ph)-ligated ruthenium hydride complexes as catalysts for formic acid dehydrogenation and carbon dioxide (CO2) hydrogenation to formate. The iPrPNPhP-ligated species is the most active for formic acid dehydrogenation, and mechanistic studies suggest that this is likely because there are kinetic advantages for catalysts that operate via the syn isomer. In CO2 hydrogenation, the iPrPNPhP-ligated species is again the most active under our optimal conditions, and we report some of the highest turnover frequencies for homogeneous catalysts. Experimental and theoretical insights into the turnover-limiting step of catalysis provide a basis for the observed trends in catalytic activity. Additionally, the stability of our complexes enabled us to detect a previously unobserved autocatalytic effect involving the base that is added to drive the reaction. Overall, by modifying the nitrogen substituent on the MACHO ligand, we have developed highly active catalysts for formic acid dehydrogenation and CO2 hydrogenation and also provided a framework for future catalyst development.

Tunable and Practical Homogeneous Organic Reductants for Cross-Electrophile Coupling.

The syntheses of four new tunable homogeneous organic reductants based on a tetraaminoethylene scaffold are reported. The new reductants have enhanced air stability compared to current homogeneous reductants for metal-mediated reductive transformations, such as cross-electrophile coupling (XEC), and are solids at room temperature. In particular, the weakest reductant is indefinitely stable in air and has a reduction potential of -0.85 V versus ferrocene, which is significantly milder than conventional reductants used in XEC. All of the new reductants can facilitate C(sp2)-C(sp3) Ni-catalyzed XEC reactions and are compatible with complex substrates that are relevant to medicinal chemistry. The reductants span a range of nearly 0.5 V in reduction potential, which allows for control over the rate of electron transfer events in XEC. Specifically, we report a new strategy for controlled alkyl radical generation in Ni-catalyzed C(sp2)-C(sp3) XEC. The key to our approach is to tune the rate of alkyl radical generation from Katritzky salts, which liberate alkyl radicals upon single electron reduction, by varying the redox potentials of the reductant and Katritzky salt utilized in catalysis. Using our method, we perform XEC reactions between benzylic Katritzky salts and aryl halides. The method tolerates a variety of functional groups, some of which are particularly challenging for most XEC transformations. Overall, we expect that our new reductants will both replace conventional homogeneous reductants in current reductive transformations due to their stability and relatively facile synthesis and lead to the development of novel synthetic methods due to their tunability.

Chemical Reduction of NiII Cyclam and Characterization of Isolated NiI Cyclam with Cryogenic Vibrational Spectroscopy and Inert-Gas-Mediated High-Resolution Mass Spectrometry.

NiII cyclam (cyclam = 1,4,8,11-tetraazacyclotetradecane) is an efficient catalyst for the selective reduction of CO2 to CO. A crucial elementary step in the proposed catalytic cycle is the coordination of CO2 to a NiI cyclam intermediate. Isolation and spectroscopic characterization of this labile NiI species without solvent has proven to be challenging, however, and only partial IR spectra have previously been reported using multiple photon fragmentation of ions generated by gas-phase electron transfer to the NiII cyclam dication at 300 K. Here, we report a chemical reduction method that efficiently prepares NiI cyclam in solution. This enables the NiI complex to be transferred into a cryogenic photofragmentation mass spectrometer using inert-gas-mediated electrospray ionization. The vibrational spectra of the 30 K ion using both H2 and N2 messenger tagging over the range 800-4000 cm-1 were then measured. The resulting spectra were analyzed with the aid of electronic structure calculations, which show strong method dependence in predicted band positions and small molecule activation. The conformational changes of the cyclam ligand induced by binding of the open shell NiI cation were compared with those caused by the spherical, closed-shell LiI cation, which has a similar ionic radius. We also report the vibrational spectrum of a NiI cyclam complex with a strongly bound O2 ligand. The cyclam ligand supporting this species exhibits a large conformational change compared to the complexes with weakly bound N2 and H2, which is likely due to significant charge transfer from Ni to the coordinated O2.

Synthesis of Triarylmethanes via Palladium-Catalyzed Suzuki-Miyaura Reactions of Diarylmethyl Esters.

The synthesis of triarylmethanes via Pd-catalyzed Suzuki-Miyaura reactions between diarylmethyl 2,3,4,5,6-pentafluorobenzoates and aryl boronic acids is described. The system operates at mild conditions and has a broad substrate scope, including the coupling of diphenylmethanol derivatives that do not contain extended aromatic substituents. This is significant as these substrates, which result in the types of triarylmethane products that are prevalent in pharmaceuticals, have not previously been compatible with systems for diarylmethyl ester coupling. Further, the reaction can be performed stereospecifically to generate stereo-inverted products. On the basis of DFT calculations, it is proposed that the oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrate occurs via an SN2 pathway, which results in the inverted products. Mechanistic studies indicate that oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrates to (IPr)Pd(0) results in the selective cleavage of the O-C(benzyl) bond in part because of a stabilizing η3-interaction between the benzyl ligand and Pd. This is in contrast to previously described Pd-catalyzed Suzuki-Miyaura reactions involving phenyl esters, which involve selective cleavage of the C(acyl)-O bond, because there is no stabilizing η3-interaction. It is anticipated that this fundamental knowledge will aid the development of new catalytic systems, which use esters as electrophiles in cross-coupling reactions.

Thermodynamic and kinetic hydricity of transition metal hydrides.

The prevalence of transition metal-mediated hydride transfer reactions in chemical synthesis, catalysis, and biology has inspired the development of methods for characterizing the reactivity of transition metal hydride complexes. Thermodynamic hydricity represents the free energy required for heterolytic cleavage of the metal-hydride bond to release a free hydride ion, H-, as determined through equilibrium measurements and thermochemical cycles. Kinetic hydricity represents the rate of hydride transfer from one species to another, as measured through kinetic analysis. This tutorial review describes the common methods for experimental and computational determination of thermodynamic and kinetic hydricity, including advice on best practices and precautions to help avoid pitfalls. The influence of solvation on hydricity is emphasized, including opportunities and challenges arising from comparisons across several different solvents. Connections between thermodynamic and kinetic hydricity are discussed, and opportunities for utilizing these connections to rationally improve catalytic processes involving hydride transfer are highlighted.

Ni(I)-Alkyl Complexes Bearing Phenanthroline Ligands: Experimental Evidence for CO2 Insertion at Ni(I) Centers.

Although the catalytic carboxylation of unactivated alkyl electrophiles has reached remarkable levels of sophistication, the intermediacy of (phenanthroline)Ni(I)-alkyl species-complexes proposed in numerous Ni-catalyzed reductive cross-coupling reactions-has been subject to speculation. Herein we report the synthesis of such elusive (phenanthroline)Ni(I) species and their reactivity with CO2, allowing us to address a long-standing question related to Ni-catalyzed carboxylation reactions.

Rational selection of co-catalysts for the deaminative hydrogenation of amides.

The catalytic hydrogenation of amides is an atom economical method to synthesize amines. Previously, it was serendipitously discovered that the combination of a secondary amide co-catalyst with (iPrPNP)Fe(H)(CO) (iPrPNP = N[CH2CH2(PiPr2)]2 -), results in a highly active base metal system for deaminative amide hydrogenation. Here, we use DFT to develop an improved co-catalyst for amide hydrogenation. Initially, we computationally evaluated the ability of a series of co-catalysts to accelerate the turnover-limiting proton transfer during C-N bond cleavage and poison the (iPrPNP)Fe(H)(CO) catalyst through a side reaction. TBD (triazabicyclodecene) was identified as the leading co-catalyst. It was experimentally confirmed that when TBD is combined with (iPrPNP)Fe(H)(CO) a remarkably active system for amide hydrogenation is generated. TBD also enhances the activity of other catalysts for amide hydrogenation and our results provide guidelines for the rational design of future co-catalysts.

Differences in the Performance of Allyl Based Palladium Precatalysts for Suzuki-Miyaura Reactions.

Palladium(II) precatalysts are used extensively to facilitate cross-coupling reactions because they are bench stable and give high activity. As a result, precatalysts such as Buchwald's palladacycles, Organ's PEPPSI species, Nolan's allyl-based complexes, and Yale's 1-tert-butylindenyl containing complexes, are all commercially available. Comparing the performance of the different classes of precatalysts is challenging because they are typically used under different conditions, in part because they are reduced to the active species via different pathways. However, within a particular class of precatalyst, it is easier to compare performance because they activate via similar pathways and are used under the same conditions. Here, we evaluate the activity of different allyl-based precatalysts, such as (η3-allyl)PdCl(L), (η3-crotyl)PdCl(L), (η3-cinnamyl)PdCl(L), and (η3-1-tert-butylindenyl)PdCl(L) in Suzuki-Miyaura reactions. Specifically, we evaluate precatalyst performance as the ancillary ligand (NHC or phosphine), reaction conditions, and substrates are varied. In some cases, we connect relative activity to both the mechanism of activation and the prevalence of the formation of inactive palladium(I) dimers. Additionally, we compare the performance of in situ generated precatalysts with commonly used palladium sources such as tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), bis(acetonitrile)dichloropalladium(II) (Pd(CH3CN)2Cl2), and palladium acetate. Our results provide information about which precatalyst to use under different conditions.

A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies.

A dual catalytic system for cross-electrophile coupling reactions between aryl halides and alkyl halides that features a Ni catalyst, a Co cocatalyst, and a mild homogeneous reductant is described. Mechanistic studies indicate that the Ni catalyst activates the aryl halide, while the Co cocatalyst activates the alkyl halide. This allows the system to be rationally optimized for a variety of substrate classes by simply modifying the loadings of the Ni and Co catalysts based on the reaction product profile. For example, the coupling of aryl bromides and aryl iodides with alkyl bromides, alkyl iodides, and benzyl chlorides is demonstrated using the same Ni and Co catalysts under similar reaction conditions but with different optimal catalyst loadings in each case. Our system is tolerant of numerous functional groups and is capable of coupling heteroaryl halides, di-ortho-substituted aryl halides, pharmaceutically relevant druglike aryl halides, and a diverse range of alkyl halides. Additionally, the dual catalytic platform facilitates a series of selective one-pot three-component cross-electrophile coupling reactions of bromo(iodo)arenes with two distinct alkyl halides. This demonstrates the unique level of control that the platform provides and enables the rapid generation of molecular complexity. The system can be readily utilized for a wide range of applications as all reaction components are commercially available, the reaction is scalable, and toxic amide-based solvents are not required. It is anticipated that this strategy, as well as the underlying mechanistic framework, will be generalizable to other cross-electrophile coupling reactions.

Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future.

Cross-coupling reactions, which were discovered almost 50 years ago, are widely used in both industry and academia. Even though cross-coupling reactions now represent mature technology, there is still a significant amount of research in this area that aims to improve the scope of these reactions, develop more efficient catalysts, and make reactions more practical. In this tutorial, a brief background to cross-coupling reactions is provided, and then the major advances in cross-coupling research over the last 20 years are described. These include the development of improved ligands and precatalysts for cross-coupling and the extension of cross-coupling reactions to a much wider range of electrophiles. For example, cross-coupling reactions are now common with sp3-hybridized electrophiles as well as ester, amide, ether, and aziridine substrates. For many of these more modern substrates, traditional palladium-based catalysts are less efficient than systems based on first-row transition metals such as nickel. Conventional cross-coupling reactions have also inspired the development of a range of related reactions, such as cross-electrophile and decarboxylative couplings as well as couplings based on metallaphotoredox chemistry. The development of these new reactions is probably at the same stage as traditional cross-coupling reactions 30 years ago, and this tutorial highlights how many of the same strategies used to improve cross-coupling reactions may also be applicable to making the new reactions more practical.