Bimolecular Substitution Research Articles

Iron-Catalyzed Cross-Electrophile Coupling for the Formation of All-Carbon Quaternary Centers.

Quaternary carbon centers are desirable targets for drug discovery and complex molecule synthesis, yet the synthesis of these motifs within traditional cross-coupling paradigms remains a significant challenge due to competing β-hydride elimination pathways. In contrast, the bimolecular homolytic substitution (SH2) mechanism offers a unique and attractive alternative pathway. Metal porphyrin complexes have emerged as privileged catalysts owing to their ability to selectively form primary metal-alkyl complexes, thereby eliminating the challenges associated with tertiary alkyl complexation with a metal center. Herein, we report an iron-catalyzed cross-electrophile coupling of tertiary bromides and primary alkyl electrophiles for the formation of all-carbon quaternary centers through a biomimetic SH2 mechanism.

Benzylic C−H Radical Sulfation by Persulfates

AbstractSulfation is a highly valuable pathological and physiological process, yet it is often underappreciated considering the rather difficult accessibility of organosulfates. O‐sulfonation (O−SO3), a conventional and still common way to make organosulfates, restricts its applicability to hydroxyl compounds and therein lies a major challenge of library construction. Here, we describe a benzylic C−H radical sulfation with persulfates via C−O bond formation. This strategy leverages modular control over the reactivity of persulfates and the stability of sulfate radicals by coutercations. K+/NH4+ stabilized sulfate radicals act as the oxidant to generate carbon‐centered radicals from substrates, and activation of persulfates by n‐NBu4+ provides O−O resource pool to facilitate C−OSO3− bond formation via a bimolecular homolytic substitution (SH2) process.

Benzylic C-H Radical Sulfation by Persulfates.

Sulfation is a highly valuable pathological and physiological process, yet it is often underappreciated considering the rather difficult accessibility of organosulfates. O-sulfonation (O-SO3), a conventional and still common way to make organosulfates, restricts its applicability to hydroxyl compounds and therein lies a major challenge of library construction. Here, we describe a benzylic C-H radical sulfation with persulfates via C-O bond formation. This strategy leverages modular control over the reactivity of persulfates and the stability of sulfate radicals by coutercations. K+/NH4 + stabilized sulfate radicals act as the oxidant to generate carbon-centered radicals from substrates, and activation of persulfates by n-NBu4 + provides O-O resource pool to facilitate C-OSO3 - bond formation via a bimolecular homolytic substitution (SH2) process.

Bimolecular Homolytic Substitution (SH2) at a Transition Metal

AbstractTransition metal‐catalyzed cross‐coupling reactions have become a powerful and widely used synthetic approach for the construction of both carbon‐carbon and carbon‐heteroatom bonds. These reactions have revolutionized synthetic chemistry by enabling the efficient formation of complex molecular architectures. Among the various methods available, the bimolecular homolytic substitution (SH2) reaction has emerged as an attractive and versatile method for the formation of C(sp3)−C(sp3) and C(sp3)‐heteroatom bonds. In recent years, significant progress has been made in the development of radical SH2 reactions, particularly those involving different transition metal complexes such as cobalt, nickel, and iron. These advancements have expanded the scope of SH2 reactions, allowing for greater diversity in substrate compatibility and reaction conditions. In this review, we aim to highlight the latest breakthroughs and mechanistic insights into radical SH2 reactions, focusing on the role of transition metal catalysts in facilitating these transformations. We will discuss the various types of transition metal complexes that have been employed, the mechanistic pathways involved, and the potential applications of these reactions in the synthesis of complex organic molecules.

A Homolytic Substitution Approach for Directing Group-Free Nickel-Catalyzed Dialkylation of Unactivated Alkenes

AbstractThe selective construction of two C(sp3)–C(sp3) bonds through trimolecular cross-coupling of unactivated alkenes remains one of the most difficult challenges in organic synthesis. Despite previous advances in metal-catalyzed coupling for the dicarbofunctionalization of alkenes, dialkylation is still problematic due to the instability of the requisite metal–alkyl intermediate, which undergoes facile β-hydride elimination or protodemetalation. Recently, our group was successful in developing a bimolecular homolytic substitution (SH2) strategy that circumvents metal–alkyl side reactions and accomplishes the challenging cross-coupling of metal–alkyl intermediates with alkyl radicals in the absence of a directing auxiliary, permitting a highly regioselective dialkylation of unactivated alkenes.1 Introduction2 Nickel-Catalyzed Dicarbofunctionalization of Unactivated Alkenes3 Nickel-Catalyzed Dialkylation of Unactivated Alkenes4 Conclusions and Perspectives

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes.

The construction of C(sp3)-C(sp3) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, we report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp3)-C(sp3) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (SH2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp3-hybridized carbon scaffolds.

Mechanistic Insights into the Proton Transfer and Substitution Dynamics of N-Atom Center Reactions: A Study of CH3O- with NH2Cl.

Bimolecular substitution reactions involving N as the central atom have continuously improved our understanding of substitution dynamics. This work used chemical dynamics simulations to investigate the dynamics of NH2Cl with N as the central atom and the multiatomic nucleophile CH3O- and compared these results with the F- + NH2Cl reaction. The most noteworthy difference is in the competition between proton transfer (PT) and the SN2 pathways. Our results demonstrate that, for the CH3O- + NH2Cl system, the PT pathway is considerably more favorable than the SN2 pathway. In contrast, no PT pathway was observed for the F- + NH2Cl system at room temperature. This can be attributed to the exothermic reaction of the PT pathway for the CH3O- + NH2Cl reaction and is coupled with a more stable transition state compared to the substitution pathway. Furthermore, the bulky nature of the CH3O- group impedes its participation in SN2 reactions, which enhances both the thermodynamic and the dynamic advantages of the PT reaction. Interestingly, the atomic mechanism reveals that the PT pathway is primarily governed by indirect mechanisms, similar to the SN2 pathway, with trajectories commonly trapped in the entrance channel being a prominent feature. These trajectories are often accompanied by prolonged and frequent proton exchange or proton abstraction processes. This current work provides insights into the dynamics of N-centered PT reactions, which are useful in gaining a comprehensive understanding of the dynamics behavior of similar reactions.

Alkene dialkylation by triple radical sorting.

The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism1-8. Biomimetic9,10 SH2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp3)-C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)-C(sp3) bonds, greatly accelerating access to complex molecules and drug-like chemical space11. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways12,13. Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a distinct mechanistic approach for alkene dialkylation.

Research on the reaction mechanism of 2,4,6‐trinitrotoluene resource utilization I: Formation of 2,4,6‐trinitrobenzoic acid in acetic acid with N,N′,N″‐trihydroxyisocyanuric acid catalyst

AbstractAs an organic molecule catalyst, N,N′,N″‐trihydroxyisocyanuric acid can selectively catalyze the oxidation of the methyl group of waste 2,4,6‐trinitrotoluene to generate 2,4,6‐trinitrobenzoic acid. This reaction can avoid environmental pollution by inorganic heavy metal catalysts. In this study, four reaction stages of this catalytic reaction were designed and validated computationally at the M06‐2X‐D3ZERO/6‐311G(d,p) level using the acetic acid solvent model. These validations include transition state searches, intrinsic reaction coordinate calculations, reactant and product optimizations, and frequency calculations. The final reaction network of 23 transition states shows that after N,N′,N″‐trihydroxyisocyanuric acid activation and common reaction, the network bifurcates into two stages: alcohol to carboxylic acid and aldehyde to carboxylic acid. Although the former stage releases about 155 kcal/mol of Gibbs free energy, less than the 177 kcal/mol from the latter stage, the overall reaction equation shows that the pathway including former stage does not consume the catalytically active substance IM_T2, which saves the energy required for reactivation and is thus more favorable. Furthermore, the key transition states in the reaction network include bimolecular substitution reactions and proton‐hopping transfer reactions. Analyses of their interaction region indicators and intrinsic reaction coordinate results demonstrate strong selectivity. Additionally, the energy barriers and heat releases of the latter are twice and 1.3 times greater than those of the former, respectively. In summary, this study elucidated two competitive reaction pathways and identified the more energetically favorable and selective pathway, and it provides useful insights for further optimization of industrial utilization of 2,4,6‐trinitrotoluene.

Origin of Stereoselectivity in SE 2' Reactions of Six-membered Ring Oxocarbenium Ions.

Oxocarbenium ions are key reactive intermediates in organic chemistry. To generate a series of structure-reactivity-stereoselectivity principles for these species, we herein investigated the bimolecular electrophilic substitution reactions (SE 2') between allyltrimethylsilane and a series of archetypal six-membered ring oxocarbenium ions using a combined density functional theory (DFT) and coupled-cluster theory approach. These reactions preferentially proceed following a reaction path where the oxocarbenium ion transforms from a half chair (3 H4 or 4 H3 ) to a chair conformation. The introduction of alkoxy substituents on six-membered ring oxocarbenium ions, dramatically influences the conformational preference of the canonical 3 H4 and 4 H3 conformers, and thereby the stereochemical outcome of the SE 2' reaction. In general, we find that the stereoselectivity in the reactions correlates to the "intrinsic preference" of the cations, as dictated by their shape. However, for the C5-CH2 OMe substituent, steric factors override the "intrinsic preference", showing a more selective reaction than expected based on the shape of the ion. Our SE 2' energetics correlate well with experimentally observed stereoselectivity, and the use of the activation strain model has enabled us to quantify important interactions and structural features that occur in the transition state of the reactions to precisely understand the relative energy barriers of the diastereotopic addition reactions. The fundamental mechanistic insight provided in this study will aid in understanding the reactivity of more complex glycosyl cations featuring multiple substituents and will facilitate our general understanding of glycosylation reactions.

Pyridine‐Boryl Radical Mediated Decarboxylative Homolytic Substitution of N‐hydroxyphthalimide Ester with Ar2X2 (X=S, Se)

AbstractHerein, we report a metal‐free approach to construct C−X (X=S, Se) bonds with the broadly available N‐hydroxyphthalimide esters and disulfides/diselenides (Ar2X2, X=S or Se) using bis(pinacolato)diboron as the reductant. Density functional theory calculations and control experiments reveal that such a C−X bond formation process is reductive decarboxylation mediated from pyridine‐boryl radical to yield alkyl or aryl radical. The resulting carbon radical then reacts with disulfides or diselenides via a bimolecular homolytic substitution (SH2) mechanism to afford the corresponding sulfides or selenides. This method displays a high functional group tolerance and broad substrate applicability.

Nickel Catalysis via SH2 Homolytic Substitution: The Double Decarboxylative Cross-Coupling of Aliphatic Acids.

Cross-coupling platforms are traditionally built around a sequence of closed-shell steps, such as oxidative addition, transmetalation, and reductive elimination. Herein, we describe a dual photo/nickel catalytic manifold that performs cross-coupling via a complementary sequence involving free radical generation, radical sorting via selective binding to a Ni(II) center, and bimolecular homolytic substitution (SH2) at a high-valent nickel-alkyl complex. This catalytic manifold enables the hitherto elusive cross-coupling of diverse aliphatic carboxylic acids to generate valuable C(sp3)-C(sp3)-products. Notably, the powerful SH2 mechanism provides general access to sterically encumbered quaternary carbon centers, addressing a long-standing challenge in fragment coupling chemistry.

Decarboxylative tandem C-N coupling with nitroarenes via SH2 mechanism

Aromatic tertiary amines are one of the most important classes of organic compounds in organic chemistry and drug discovery. It is difficult to efficiently construct tertiary amines from primary amines via classical nucleophilic substitution due to consecutive overalkylation. In this paper, we have developed a radical tandem C-N coupling strategy to efficiently construct aromatic tertiary amines from commercially available carboxylic acids and nitroarenes. A variety of aromatic tertiary amines can be furnished in good yields (up to 98%) with excellent functional group compatibility under mild reaction conditions. The use of two different carboxylic acids also allows for the concise synthesis of nonsymmetric aromatic tertiary amines in satisfactory yields. Mechanistic studies suggest the intermediacy of the arylamine–(TPP)Fe(III) species and might provide a possible evidence for an SH2 (bimolecular homolytic substitution) pathway in the critical C-N bond formation step.

Does Steric Hindrance Actually Govern the Competition between Bimolecular Substitution and Elimination Reactions?

Bimolecular nucleophilic substitution (SN2) and elimination (E2) reactions are prototypical examples of competing reaction mechanisms, with fundamental implications in modern chemical synthesis. Steric hindrance (SH) is often considered to be one of the dominant factors determining the most favorable reaction out of the SN2 and E2 pathways. However, the picture provided by classical chemical intuition is inevitably grounded on poorly defined bases. In this work, we try to shed light on the aforementioned problem through the analysis and comparison of the evolution of the steric energy (EST), settled within the IQA scheme and experienced along both reaction mechanisms. For such a purpose, the substitution and elimination reactions of a collection of alkyl bromides (R-Br) with the hydroxide anion (OH–) were studied in the gas phase at the M06-2X/aug-cc-pVDZ level of theory. The results show that, generally, EST recovers the appealing trends already anticipated by chemical intuition and organic chemistry, supporting the role that SH is classically claimed to play in the competition between SN2 and E2 reactions.

Transition-Metal-Free Synthesis of Unsymmetrical Diaryl Tellurides via SH2 Reaction of Aryl Radicals on Tellurium.

Although diaryl tellurides are parent organotellurium compounds, their synthesis methods, especially for unsymmetrical ones, are limited. This may be due to the instability of diaryl tellurides and their synthesis intermediates under reaction conditions. Radical reactions are known to exhibit excellent functional group selectivity; therefore, we focused on a bimolecular homolytic substitution (SH2) reaction between the aryl radical and diaryl ditelluride. Aryl radicals are generated from arylhydrazines in air and captured by diaryl ditellurides, resulting in a selective formation of unsymmetrical diaryl tellurides with high yields. The electronic effects of the substituents on both arylhydrazines and diaryl ditellurides on the SH2 reaction of tellurium are also discussed in detail.

Catalytic, contra-Thermodynamic Positional Alkene Isomerization.

The positional isomerization of C═C double bonds is a powerful strategy for the interconversion of alkene regioisomers. However, existing methods provide access to thermodynamically more stable isomers from less stable starting materials. Here, we report the discovery of a dual catalyst system that promotes contra-thermodynamic positional alkene isomerization under photochemical irradiation, providing access to terminal alkene isomers directly from conjugated, internal alkene starting materials. The utility of the method is demonstrated in the deconjugation of diverse electron-rich/electron-poor alkenes and through strategic application to natural product synthesis. Mechanistic studies are consistent with a regiospecific bimolecular homolytic substitution (SH2') mechanism proceeding through an allyl-cobaloxime intermediate.

Experimental and Theoretical Study on the Gas-Phase Reactions of Germyl Radicals with NF3: Homolytic Substitution at the Nitrogen Atom vs Fluorine Abstraction.

In this paper, we report on the unexplored reaction mechanisms of bimolecular homolytic substitution (SH2) between GeH3 radicals and the nitrogen atom of NF3. The SH2 reactions are studied both experimentally and theoretically with ab initio and density functional theory (DFT) calculations. The experimental results of X-ray irradiation of mixtures of GeH4 and NF3 show the formation of GeH3–NF2 and GeH3–F. The trend of product yields as a function of the increase in GeH4 partial pressure in the irradiated mixtures evidences the predominant role of GeH3 radicals. Particularly, the SH2 mechanism can be hypothesized for the reaction between GeH3 radicals and NF3 molecules leading to GeH3–NF2. This mechanism is further confirmed by the increase in GeH3–NF2 yield observed if O2 is added, as a radical scavenger, to the reaction mixture. In agreement with the experimental data, from the calculations performed at the CCSD(T) and G3B3 levels of theory, we observe that the GeH3–NF2 product actually occurs from a bimolecular homolytic substitution by the GeH3 radical, which attacks the N atom of NF3, and this reaction is in competition with the fluorine abstraction reaction leading to GeH3F, even if other mechanisms may be involved in the formation of this product.

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study.

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition–elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

Asymmetric Electrophilic Reactions in Phosphorus Chemistry

This review is devoted to the theoretic and synthetic aspects of asymmetric electrophilic substitution reactions at the stereogenic phosphorus center. The stereochemistry and mechanisms of electrophilic reactions are discussed—the substitution, addition and addition-elimination of many important reactions. The reactions of bimolecular electrophilic substitution SE2(P) proceed stereospecifically with the retention of absolute configuration at the phosphorus center, in contrast to the reactions of bimolecular nucleophilic substitution SN2(P), proceeding with inversion of absolute configuration. This conclusion was made based on stereochemical analysis of a wide range of trivalent phosphorus reactions with typical electrophiles and investigation of examples of a sizeable number of diverse compounds. The combination of stereospecific electrophilic reactions and stereoselective nucleophilic reactions is useful and promising for the further development of organophosphorus chemistry. The study of phosphoryl group transfer reactions is important for biological and molecular chemistry, as well as in studying mechanisms of chemical processes involving organophosphorus compounds. New versions of asymmetric electrophilic reactions applicable for the synthesis of enantiopure P-chiral secondary and tertiary phosphines are discussed.