Steric Properties Research Articles

Asymmetric Synthesis of Dialkyl Carbinols by Ni-Catalyzed Reductive-Oxidative Relay of Distinct Alkenes.

Enantioenriched unsymmetric dialkyl carbinol derivatives are of importance in natural products, bioactive molecules, and functional organic materials. However, the catalytic asymmetric synthesis of dialkyl carbinol derivatives remains challenging due to the similar steric and electronic properties of two alkyl substituents. Herein, an unprecedented synthesis of chiral dialkyl carbinol ester derivatives from Ni-catalyzed reductive-oxidative relay cross-coupling of two alkenes is developed for the first time. The reaction features the use of enol esters and unactivated alkenes as two different alkyl equivalents to undergo head-to-tail and enantioselective alkyl-alkyl cross-coupling. The reaction undergoes two-electron reduction and single electron oxidation in the presence of both reductants and oxidants. The use of an allyl bromide as single electron acceptor is crucial for the success of this non-trivial asymmetric cross-coupling, providing a new reaction mode for asymmetric alkyl-alkyl bond-forming event in the absence of stoichiometric alkyl electrophiles.

Modular Synthesis of Monoanionic PN Ligands Leads to Unexpected Structural Diversity in Lanthanum Chemistry.

We report a new synthetic entry to a series of N-substituted anilidophosphine ligands (short HPNR, R = pTol (HPNTol), 3,5-dimethylphenyl (HPN3,5Me), 3,5-bis(trifluoromethyl)phenyl (HPN3,5CF3), 2-methoxyphenyl (HPNOMe), diisopropylphenyl (HPNDipp), and adamantyl (HPNAd)), allowing a detailed tuning of their steric (and electronic) properties. HPNR could be converted into their lithium salts LiPNR, which are effective precursors for salt metathesis reactions. The new ligands are used for the synthesis of an array of lanthanide complexes using LaCl3(THF)1.2 as a precursor. Depending on the steric bulk of the anilidophosphine ligand, either chloride-bridged dimers of the general formula [(PNR)2La(μ-Cl2)La(PNR)2] (R = pTol (3f), 3,5-dimethylphenyl (3d) and adamantyl (3a)) or mononuclear complexes of the general formula (PNR)2LaCl (R = diisopropylphenyl (3e)) are observed, if the complexation reaction is carried out in toluene. Contrary, if salt metathesis reactions are carried out in dimethoxyethane (DME) as a coordinating solvent, -ate complexes of the general formula [(PNR)2La(μ-Cl2)Li(DME)] (R = Adamantyl (4a) and R = 2-methoxyphenyl (4d)) or [Li(DME)3][(PNR)2LaCl2] (R = 3,5-bis(trifluoromethyl)phenyl (4b), R = pTol (4f) and R = 3,5-dimethylphenyl (4d)) are observed. All ligands and complexes have been thoroughly characterized by 1D and 2D NMR spectroscopy, IR, and X-ray crystallography. Finally, the steric demand of the new anilidophosphine ligands is evaluated using SambVca simulations.

The structure of tetranuclear zirconium pivalate ZR<sub>4</sub>O<sub>2</sub> [(CH<sub>3</sub>)<sub>3</sub>CCO<sub>2</sub>]<sub>12</sub> according to X-ray diffraction analysis and quantum chemical calculations

The crystal and molecular structure of a polynuclear pivalate complex obtained by the interaction of ZrCl4 with pivalic acid was determined by X-ray diffraction analysis. The compound C71H124O28Zr4 (compound 1) crystallizes in the monoclinic crystal system. The crystal structure was refined in the nonstandard space group I2. The asymmetric part of the structure includes three Zr atoms, six pivalate ligands, a bridging µ3-O oxygen atom, as well as disordered crystallization molecules of pivalic acid with an occupancy of 50% and benzene with an occupancy of 50%. The zirconium complex molecule is a tetranuclear cluster that contains three types of Zr atoms that differ in ligand environment. Comparison of the results of quantum chemical calculations of the model reaction ZrCl4 with acetic acid with the literature data on reactions of ZrCl4 with aliphatic acids have shown the possibility of the formation of both mononuclear Zr(RCO2)4 and polynuclear clusters in this reaction, which is a new route for obtaining polynuclear zirconium clusters. The structure of the clusters formed depends on the steric properties of carboxylate ligands.

Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads

There has been a surge of interest in covalent inhibitors for protein kinases in recent years. Despite success in oncology, the off-target reactivity of these molecules is still hampering the use of covalent warhead-based strategies. Herein, we disclose the development of precision-guided warheads to mitigate the off-target challenge. These reversible warheads have a complex and cyclic structure with optional chirality center and tailored steric and electronic properties. To validate our proof-of-concept, we modified acrylamide-based covalent inhibitors of c-Jun N-terminal kinases (JNKs). We show that the cyclic warheads have high resilience against off-target thiols. Additionally, the binding affinity, residence time, and even JNK isoform specificity can be fine-tuned by adjusting the substitution pattern or using divergent and orthogonal synthetic elaboration of the warhead. Taken together, the cyclic warheads presented in this study will be a useful tool for medicinal chemists for the deliberate design of safer and functionally fine-tuned covalent inhibitors.

Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold

For mitogen-activated protein kinases (MAPKs) a shallow surface—distinct from the substrate binding pocket—called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the protein-protein interactions of MAPKs. The electronic and steric properties of the Michael acceptor can be tailored via different substitution patterns. The inversion of the chiral center of the warhead can reroute chemical bond formation with the targeted cysteine towards the neighboring, but less nucleophilic histidine. Compounds bind to the shallow MAPK D-groove with low micromolar affinity in vitro and perturb MAPK signaling networks in the cell. This class of chiral, cyclic and enhanced 3D shaped Michael acceptor scaffolds offers an alternative to conventional ATP-competitive drugs modulating MAPK signaling pathways.

Bornylimidazo[1,5‑a]pyridin-3-ylidene allylic Pd catalyst with optimal electronic and steric properties for synthesis of 3,3’-disubstituted oxindoles

Bornylimidazo[1,5‑a]pyridin-3-ylidene allylic Pd catalyst with optimal electronic and steric properties for synthesis of 3,3’-disubstituted oxindoles

Synthesis of Monodehydro-Diketopiperazines Enabled by Cp*Rh(III)-Catalyzed Amine-Directed N-H Functionalization.

A two-step, diversity-building sequence to prepare monodehydro-diketopiperazines from readily accessible materials is reported. Rh(III)-catalyzed, amine-directed N-H functionalization of a variety of α-amino amides with a diazophosphonate ester and subsequent cyclization gives phosphonate-substituted diketopiperazines. A Horner-Wadsworth-Emmons reaction then provides monodehydro-diketopiperazines with high E-alkene selectivity. This transformation was used to incorporate a variety of groups originating from diverse aldehydes and ketones with different steric and electronic properties. Face-selective hydrogenation to diketopiperazines is also disclosed.

Heteroatoms‐Stabilized Single Palladium Atoms on Amorphous Zeolites: Breaking the Tradeoff between Catalytic Activity and Selectivity for Alkyne Semihydrogenation

AbstractAs a fundamental industrial catalytic process, the semihydrogenation of alkynes presents a challenge in striking a balance between activity and selectivity due to the issue of over‐hydrogenation. Herein, we develop an efficient catalytic system based on single‐atom Pd catalysts supported on boron‐containing amorphous zeolites (Pd/AZ−B), achieving the tradeoff breaking between the activity and selectivity for the selective hydrogenation of alkynes. Advanced characterizations and theoretical density functional theory calculations confirm that the incorporated B atoms in the Pd/AZ−B can not only alter the geometric and electronic properties of Pd atoms by controlling the electron migration from Pd but also mitigate the interaction between alkene and the catalyst supports. This boosts the exceptional catalytic efficacy in the semihydrogenation of phenylacetylene to styrene under mild conditions (298 K, 2 bar H2), achieving a recorded turnover frequency (TOF) value of 24198 h−1 and demonstrating 95 % selectivity to styrene at full conversion of phenylacetylene. By comparison, the heteroatom‐free amorphous zeolite‐anchored Pd nanoparticles and the commercial Lindlar catalyst have styrene selectivities of 73 % and 15 %, respectively, under identical reaction conditions. This work establishes a solid foundation for developing highly active and selective hydrogenation catalysts by controllably optimizing their electronic and steric properties.

Heteroatoms-Stabilized Single Palladium Atoms on Amorphous Zeolites: Breaking the Tradeoff between Catalytic Activity and Selectivity for Alkyne Semihydrogenation.

As a fundamental industrial catalytic process, the semihydrogenation of alkynes presents a challenge in striking a balance between activity and selectivity due to the issue of over-hydrogenation. Herein, we develop an efficient catalytic system based on single-atom Pd catalysts supported on boron-containing amorphous zeolites (Pd/AZ-B), achieving the tradeoff breaking between the activity and selectivity for the selective hydrogenation of alkynes. Advanced characterizations and theoretical density functional theory calculations confirm that the incorporated B atoms in the Pd/AZ-B can not only alter the geometric and electronic properties of Pd atoms by controlling the electron migration from Pd but also mitigate the interaction between alkene and the catalyst supports. This boosts the exceptional catalytic efficacy in the semihydrogenation of phenylacetylene to styrene under mild conditions (298 K, 2 bar H2), achieving a recorded turnover frequency (TOF) value of 24198 h-1 and demonstrating 95 % selectivity to styrene at full conversion of phenylacetylene. By comparison, the heteroatom-free amorphous zeolite-anchored Pd nanoparticles and the commercial Lindlar catalyst have styrene selectivities of 73 % and 15 %, respectively, under identical reaction conditions. This work establishes a solid foundation for developing highly active and selective hydrogenation catalysts by controllably optimizing their electronic and steric properties.

Protective effect of the perchlorophenyl group in organophosphorus chemistry

The homoleptic phosphine with the bulky perchlorophenyl group, (C6Cl5)3P (1), exhibits trigonal pyramidal structure (TPY-3), yet considerably flattened: Σ(C–P–C') = 321.0(1)°. Key steric and electronic properties of this simple organophosphorus species have been estimated by calculation. Attending to its characteristic features, 1 can be rated as a deactivated phosphine, where the less-basic P atom is sterically shielded by the bulky C6Cl5 groups. This marked inertness notwithstanding, it has been possible to obtain (under harsh conditions) derivatives with phosphorus in high oxidation state, namely the phosphine oxide (C6Cl5)3PO (2) and the difluorophosphorane (C6Cl5)3PF2 (3). These four- and five-substituted derivatives respectively exhibit trigonal pyramidal (TPY-4) and trigonal bipyramidal (TBPY-5) structures. The Σ(C–P–C') value steadily increases along the series 1–3, according to the referred structural variation. The P–C bond length is, in turn, invariably maintained at about 185 pm regardless of the different oxidation state, the increasing number of substituents around the P atom and the overall geometry. The hypervalent difluorophosphorane (C6Cl5)3PF2 (3) dissociates one of the axial fluorides in the gas phase giving rise to the fluorophosphonium cation [(C6Cl5)3PF]+, as detected by mass spectrometry. This cation is identified as a Lewis superacid.

Platinum(II) acetimino cyclometalated complexes derived from room temperature ammonia activation

Two Pt(II) rollover cyclometalated complexes, [Pt(bpyPh‐H)(DMSO)Me] (1) and [Pt(bpyPh‐H)(DMSO)Cl] (2), where bpyPh‐H is the C3‐deprotonated 6‐phenyl‐2,2’‐bipyridine, were reacted with aqueous ammonia in acetone at room temperature. In the case of the electron‐poor complex 2 simple substitution of DMSO gave the amino complex [Pt(bpyPh‐H)(NH3)Cl] (4), whereas the electron‐rich complex 1 produced the rare acetimine complex [Pt(bpyPh‐H)(HN=CMe2)Me] (3), stable both in solution and in the solid state. The result is noteworthy, as the condensation product of acetone and ammonia, acetimine, is not stable under mild conditions. The reaction likely requires a Pt(II) electron‐rich complex and the presence of a carbon donor in trans position. An analogous reaction occurs with methylamine, allowing the synthesis of the secondary imine complex [Pt(bpyPh‐H)(MeN=CMe2)Me], 5. Starting from this finding a series of cyclometalated acetimine complexes [Pt(N^C)(HN=CMe2)Me] were isolated and characterized with other classical and rollover cyclometalated ligands with an array of different electronic and steric properties, indicating a possible extension of the reaction to various cyclometalated ligands. A preliminary study on the antimicrobial and antitumor properties of complex 3, taken as a model for this class, showed no significant effects against Gram‐positive, Gram‐negative bacteria, or yeasts, but found activity in vitro against HT29 colon cancer cell line.

IPr*F - Highly Hindered, Fluorinated N-Heterocyclic Carbenes.

The introduction of fluorine atom has attracted considerable interest in molecular design owing to the high electronegativity and the resulting polarization of carbon-fluorine bonds. Simultaneously, sterically-hindered N-heterocyclic carbenes (NHCs) have received major interest due to high stabilization of the reactive metal centers, which has paved the way for the synthesis of stable and reactive organometallic compounds with broad applications in main group chemistry, inorganic synthesis and transition-metal-catalysis. Herein, we report the first class of sterically-hindered, fluorinated N-heterocyclic carbenes. These ligands feature variable fluorine substitution at the N-aromatic wingtip, permitting to rationally vary steric and electronic characteristics of the carbene center imparted by the fluorine atom. An efficient, one-pot synthesis of fluorinated IPr*F ligands is presented, enabling broad access of academic and industrial researchers to the fluorinated ligands. The evaluation of steric, electron-donating and π-accepting properties as well as coordination chemistry to Au(I), Rh(I) and Se is presented. Considering the unique properties of carbon-fluorine bonds, we anticipate that this novel class of fluorinated carbene ligands will find widespread application in stabilizing reactive metal centers.

Synthesis, Characterization, and Catalysis of Planar Chiral Ferrocene‐based N‐Heterocyclic Carbene Ligands and Its Metal Complexes

This study presents the development of a novel planar chiral ferrocene‐based NHC ligand and its corresponding metal complexes. The key unit of the imidazolium backbone, planar chiral ortho‐isopropyl ferrocenyl amine, was synthesized starting from (R)‐Ugi's amine. Imidazolium was obtained through the sequential condensation of glyoxal with ferrocenyl amine, followed by the ring‐closure of 1,3‐diferrocenyldiimine with chloromethylethyl ether. Chiral imidazolylidene NHC (IFcPr) metal complexes were prepared by treating imidazolium with silver oxide or base followed by transmetalation with appropriate metal salts. The steric and electronic properties of the IFcPr ligand were assessed using %Vbur and TEP, respectively. These assessments indicated that the ligand was as bulky as the adamantyl NHC ligand and exhibited strong donor ability similar to that of a triazolylidene NHC ligand. The catalytic performance of the copper and palladium complexes was evaluated in the asymmetric borylation of ethyl cinnamate and Suzuki–Miyaura coupling reactions, respectively. The IFcPr‐Cu complex catalyzed the borylation of ethyl cinnamate with bis(pinacolato) diboron, followed by oxidation to yield the hydroxy ester with 58% yield and 30% ee. In contrast, the IFcPr‐Pd‐PEPPSI complex provided the axial chiral binaphthyl compound with 59% yield and 51% ee at a low catalyst loading (0.1 mol%, TON = 590).

N‐Heterocyclic Carbene–Based Catalysts for Glycerol Valorisation: Current State and Perspectives

ABSTRACTN‐Heterocyclic carbenes (NHCs) are molecules with exceptional catalytic properties in a wide range of reactions. Recently, there has been a growing interest in using them as catalysts for biomass conversion. In this review, we examine the current state of glycerol valorisation (GV) using several catalytic systems, including metallic complexes bearing NHCs as ligands, polymeric building blocks and organocatalysts. The study covers literature published in the last 15 years, detailing the catalyst scope, reaction conditions and products of GV. This analysis emphasises the importance of varying the steric and electronic properties of NHCs within the reviewed catalytic systems. Furthermore, a critical evaluation of the proposed mechanistic pathways complements these results. A comprehensive understanding of the challenges of using such catalytic systems will emerge by compiling literature on the use of NHCs for the studied reactions. Additionally, this will promote new opportunities for further research in both academic and industrial fields.

Photocatalytic Direct Para‐Selective C−H Amination of Benzyl Alcohols: Selectivity Independent of Side Substituents

AbstractAminoarenes are important molecules for broad applications in nearly all modern industries that involve chemicals. Direct and site‐selective C−H bond amination of arenes provides the most efficient and convenient method to prepare aminoarenes. A main challenge is to selectively install the amino group (or other functional groups) to the distal para‐carbon of arenes (especially multi‐substituted arenes) during the C−H bond functionalization events. Herein, we address this problem by designing a new strategy via a sequential radical dearomatization/radical amination/rearomatization process for para‐selective amination of benzyl alcohols. The para‐selectivity of our reaction is completely independent of the electronic and steric properties of the other substituents of the arene substrates. Aminoarenes with many substituents (up to full substitution) and diverse substitution patterns, including those difficult to synthesize previously, could be readily prepared using our protocols. Further exploration of the current strategy shall lead to other challenging C−H functionalization of arenes.

Photocatalytic Direct Para-Selective C-H Amination of Benzyl Alcohols: Selectivity Independent of Side Substituents.

Aminoarenes are important molecules for broad applications in nearly all modern industries that involve chemicals. Direct and site-selective C-H bond amination of arenes provides the most efficient and convenient method to prepare aminoarenes. A main challenge is to selectively install the amino group (or other functional groups) to the distal para-carbon of arenes (especially multi-substituted arenes) during the C-H bond functionalization events. Herein, we address this problem by designing a new strategy via a sequential radical dearomatization/radical amination/rearomatization process for para-selective amination of benzyl alcohols. The para-selectivity of our reaction is completely independent of the electronic and steric properties of the other substituents of the arene substrates. Aminoarenes with many substituents (up to full substitution) and diverse substitution patterns, including those difficult to synthesize previously, could be readily prepared using our protocols. Further exploration of the current strategy shall lead to other challenging C-H functionalization of arenes.

Tuning the Steric and Electronic Properties of Hemilabile NHC ligands for Gold(I/III) Catalyzed Oxyarylation of Ethylene: A Computational Study.

Mechanistic studies on 1,2-oxyarylation of ethylene promoted by gold catalysts bearing hemilabile N-Heterocyclic Carbene (NHC^X) ligands were conducted by DFT calculations, exploring the whole catalytic cycle. After highest energy transition state (TS) barriers were located for NHC^N gold catalyst, and experimental results with different iodoarenes and alcohols rationalized, the study was extended to modified NHC^X catalysts, to observe how electronic and steric effects could affect the rate determining step TS. Electronic effects were investigated on NHC^X (X = H, N, O, P, and S), whereas steric effects emerged when comparing catalysts with different N-R groups (R = Dipp, Mes, tBu and Me). Finally, we suggest a different catalyst design based on N-aryl N-o-donor-aryl NHC, with different donors and NHC backbones to search for better performing systems.

Identity of the Silyl Ligand in an Iron Silyl Complex Influences Olefin Hydrogenation: An Experimental and Computational Study.

In this study, we explore the selective synthesis of iron silyl complexes using the reaction of an iron mesityl complex (MesCCC)FeMes(Py) with various hydrosilanes. These resulting iron silyl complexes, (MesCCC)Fe(SiH2Ph)(Py)(N2), (MesCCC)Fe(SiMe2Ph)(Py)(N2), and (MesCCC)Fe[SiMe(OSiMe3)2](Py)(N2), serve as effective precatalysts for olefin hydrogenation. The key to their efficiency in catalysis lies in the specific nature of the silyl ligand attached to the iron center. Experimental observations, supported by density functional theory (DFT) simulations, reveal that the catalytic performance correlates with the relative stability of dihydrogen and hydride species associated with each iron silyl complex. The stability of these intermediates is crucial for efficient hydrogen transfer during the catalytic cycle. The DFT simulations help to quantify these stability factors, showing a direct relationship between the silyl ligand's electronic and steric properties and the overall catalytic activity. Complexes with certain silyl ligands exhibit better performance due to the optimal balance between the stability and reactivity of the key active catalyst. This work highlights the importance of ligand design in the development of iron-based hydrogenation catalysts.

A FAIR comparison of activated carbon, biochar, cyclodextrins, polymers, resins, and metal organic frameworks for the adsorption of per- and polyfluorinated substances

Per- and polyfluorinated substances (PFAS) have complex sorption behaviors, complicating removal from water and selection of suitable adsorbents. We evaluated adsorption of 44 PFAS across four adsorbent groups: activated carbon and biochar (AC and BC), cyclodextrin-based adsorbents (cyclodextrins), polymer-based adsorbents and resins, and inorganic adsorbents and metal organic frameworks (MOFs). We analyzed over 500 adsorption coefficients (Kd) from literature, calculated at aqueous equilibrium concentration of 1 ± 0.3 µg/L under comparable experimental conditions. On average, Kd of AC and BC exceeded 107 L/kg for PFAS with C-F bonds > 7, unlike other adsorbents with Kd < 107. This trend holds for C-F bonds ≥ 4. Cyclodextrins, polymer-based adsorbents and resins outperform AC and BC for C-F bonds < 4. For AC and BC, Kd follows the order PFOS>PFOA>PFBS>PFBA, with adsorption increasing with increasing point of zero charge of the adsorbent. For AC and BC, as well as cyclodextrins, Kd values were related to PFAS hydrophobicity and steric properties. Additionally, adsorption was influenced by head group type, non-fluorinated carbon atoms, and the presence of oxygen and/or chlorine in the PFAS. No clear relationship was found for the other adsorbents. Adsorption prediction using a Random Forest Regressor and literature data was feasible for AC and BC, but not for other adsorbents. Cyclodextrins outperform AC and BC for removing PFAS across varying mobilities from water, whereas AC and BC are superior for low mobility PFAS. To support further data use all data and code used are freely available, following FAIR data principles.

Hemilabile and Redox-Active Quinone Ligands Unlock sp3-Rich Couplings in Nickel-Catalyzed Olefin Carbosulfenylation.

A three-component coupling approach toward structurally complex dialkylsulfides is described via the nickel-catalyzed 1,2-carbosulfenylation of unactivated alkenes with organoboron nucleophiles and alkylsulfenamide (N-S) electrophiles. Efficient catalytic turnover is facilitated using a tailored N-S electrophile containing an N-methyl methanesulfonamide leaving group, allowing catalyst loadings as low as 1 mol%. Regioselectivity is controlled by a collection of monodentate, weakly coordinating native directing groups, including sulfonamides, amides, sulfinamides, phosphoramides, and carbamates. Key to the development of this transformation is the identification of quinones as a family of hemilabile and redox-active ligands that tune the steric and electron properties of the metal throughout the catalytic cycle. DFT calculations show that the duroquinone (DQ) ligand adopts different coordination modes in different stages of the Ni-catalyzed 1,2-carbosulfenylation-binding as an η6 capping ligand to stabilize the precatalyst/resting state and prevent catalyst decomposition, binding as an X-type redox-active durosemiquinone radical anion to promote alkene migratory insertion with a less distorted square planar Ni(II) center, while binding as an η1 L-type ligand to promote N-S oxidative addition at a relatively more electron-rich and sterically less crowded Ni(I) center.