Steric Requirements Research Articles

Diborane, Diborene and M(I)‐η2‐Diborene Complexes Stabilized by Bicyclic (Alkyl)(Amino)Carbene (M=Cu and Ag)

AbstractBICAAC (bicyclic (alkyl)(amino)carbene) as ambiphilic carbene has been utilized to prepare stable neutral tetrahydrodiborane [BICAAC (H2)B−B(H2) BICAAC] and dihydrodiborene [BICAAC→(H)B=B(H) BICAAC] compounds. The Lewis base stabilized dihydrodiborene is isoelectronic and isolobal to conventional olefins and therefore offers the possibility to explore the formation of π‐complexes with transition metals. Reaction of the diborene with coinage metal salts (CuCl, AgBr and CuI) leads to the formation of π‐diborene metal complexes via η2 side‐on coordination. These are first examples of dihydrodiborene coinage metal complexes. Interestingly, coordination of two CuCl units to the diborene has been observed for the first time with a considerable lengthening of >B=B< and B CBICAAC bonds manifesting the key role of the BICAAC combined with small steric requirements of hydride substituents in stabilizing these complexes. The energy decomposition analysis (EDA) calculations reveal the interaction between the diborene and Cu(I)/Ag(I) is mainly electrostatic in nature.

Tri‐ and Hexadentate Poly‐Lewis Acids – Attempts to Unravel the Complex Dynamics of Cage and Capsule Formation in Solution

AbstractTwo tri‐ and two hexadentate poly‐Lewis acids (PLAs) with calyx‐like structures of C3 symmetry containing aluminum‐ and boron‐containing Lewis acidic functions were prepared by tin‐metal exchange reactions. The triply hydrosilylated [12]annulene served as basic framework. It forms a calyx‐like structure by the stereo‐ and regioselective attachment of three SiMeCl2 groups to the planar [12]annulene. The PLA precursors were generated by attaching three or six trimethylstannylethynyl groups to the silicon atoms. Lewis acid functions were introduced using the reagents bis‐(bis(trimethylsilyl)methyl)aluminium hydride (HAl[CH(SiMe3)2]2) and catecholatochloroborane (ClBCat). The complexation behavior of the PLAs towards different Lewis bases was investigated by NMR. Bases included pyridine, polydentate nitrogen‐ and phosphorus‐containing bases. Additionally, three molecules of a bidentate phosphorus‐containing base were captured with hexadentate PLAs. Diffusion NMR experiments provided insight into the aggregation processes: some of the adducts had a significantly larger volume than expected, indicating the formation of larger adducts than the expected 1 : 1 adduct, including larger 2 : 2 adduct cages. The distances between the Lewis acid units and the steric requirement of the attached substituents determine the complexation behavior of the PLAs. Thus, the weak Lewis acidic BCat units show no (tridentate case) or a strong (hexadentate case) interaction with PMe2‐containing bases, if they can act cooperatively.

Isolation and Electronic Structures of Lanthanide(II) Bis(trimethylsilyl)phosphide Complexes.

While lanthanide (Ln) silylamide chemistry is mature, the corresponding silylphosphide chemistry is underdeveloped, with [Sm{P(SiMe3)2}{μ-P(SiMe3)2}3Sm(THF)3] being the sole example of a structurally authenticated Ln(II) silylphosphide complex. Here, we expand the Ln(II) {P(SiMe3)2} chemistry through the synthesis and characterization of nine complexes. The dinuclear "ate" salt-occluded complexes [{Ln[P(SiMe3)2]3(THF)}2(μ-I)K3(THF)] (1-Ln; Ln = Sm, Eu) and polymeric "ate" complex [KYb{P(SiMe3)2}3{μ-K[P(SiMe3)2]}2]∞ (2-Yb) were prepared by the respective salt metathesis reactions of parent [LnI2(THF)2] (Ln = Sm, Eu, Yb) with 2 or 3 equiv of K{P(SiMe3)2} in diethyl ether. The separate treatment of these complexes with either pyridine or 18-crown-6 led to the formation of the mononuclear solvated adducts trans-[Ln{P(SiMe3)2}2(py)4] (3-Ln; Ln = Sm, Eu, Yb) and [Ln{P(SiMe3)2}2(18-crown-6)] (4-Ln; Ln = Sm, Eu, Yb), with concomitant loss of K{P(SiMe3)2}. The complexes were characterized by a combination of NMR, electron paramagnetic resonance (EPR), attenuated total reflectance infrared (ATR-IR), electronic absorption and emission spectroscopies, elemental analysis, SQUID magnetometry, and single crystal X-ray diffraction. We find that these complexes contrast with those of related Ln(II) bis(silyl)amide complexes due to differences in ligand donor atom hardness and ligand steric requirements from Ln-P bonds being longer than Ln-N bonds. This leads to higher coordination numbers, shorter luminescence lifetimes, and smaller easy-axis magnetic anisotropy parameters.

Cyanohydrin Equilibria Implicate Non-Aromatic Aldehydes in Photochemical Production of Oceanic Carbon Monoxide.

Carbonyls have previously been dismissed as significant precursors for carbon monoxide (CO) photoproduction from natural chromophoric dissolved organic matter (CDOM). Here, we used hydrogen cyanide (HCN), which reacts with carbonyls to form photochemically inert cyanohydrins, as a probe to re-examine the role of carbonyls in CO photoproduction. Adding HCN to low-absorbance euphotic zone seawater decreased CO photoproduction. Modeling [HCN] (∼5 to 364 μM) vs the percent decrease in CO photoproduction (%CO↓) yielded carbonyl-cyanohydrin dissociation equilibrium constants, KD, and maximum %CO↓, %CO↓max values. Four Atlantic and Pacific seawater KDs (66.7 ± 19.6 μM) overlap aqueous aliphatic but not aromatic aldehyde KDs. Phenylacetaldehyde (PA) and other β,γ-unsaturated aldehydes are proposed as prototypical CO precursors. Direct photolysis of ∼10 nM PA can supply the measured daily production of HCN-sensitive CO at an open-ocean site near Bermuda. HCN's %CO↓max was 31 ± 2.5% in North Atlantic seawater vs the 13 ± 2.5% inhibition of CO photoproduction by borohydride, a dilemma since only borohydride affects most ketones. Borohydride also decreased CDOM absorption much more than did HCN. This puzzle probably reflects differing steric and solvation requirements in HCN- and borohydride-CDOM reactions. This study demonstrates cyanophilic aldehydes to be a significant source of open-ocean CO and reveals new clues regarding CDOM photochemistry mechanisms.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides

Despite recent advancements in catalytic synthesis of axial chirality, reports on non‐biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho‐aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Metal-Organic Layers with Photosensitizer and Pyridine Pairs Activate Alkyl Halides for Photocatalytic Heck-Type Coupling with Olefins.

Photochemical generation of alkyl radicals from haloalkanes often requires strong energy input from ultraviolet light or a strong photoreductant. Haloalkanes can alternatively be activated with nitrogen-based nucleophiles through a sequential SN2 reaction and single-electron reduction to access alkyl radicals, but these two reaction steps have opposite steric requirements on the nucleophiles. Herein, we report the design of Hf12 metal-organic layers (MOLs) with iridium-based photosensitizer bridging ligands and secondary-building-unit-supported pyridines for photocatalytic alkyl radical generation from haloalkanes. By bringing the photosensitizer and pyridine pairs in proximity, the MOL catalysts allowed facile access to the pyridinium salts from SN2 reactions between haloalkanes and pyridines and at the same time enhanced electron transfer from excited photosensitizers to pyridinium salts to facilitate alkyl radical generation. Consequentially, the MOLs efficiently catalyzed Heck-type cross-coupling reactions between haloalkanes and olefinic substrates to generate functionalized alkenes. The MOLs showed 4.6 times higher catalytic efficiency than the homogeneous counterparts and were recycled and reused without a loss of catalytic activity.

A Concise Enantioselective Synthesis of Fluorinated Pyrazolo-Piperidine GSK3901383A Enabled by an Organocatalytic Aza-Michael Addition.

A highly enantioselective organocatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl (E)-2,2-difluoro-5-oxopent-3-enoate has been developed. This reaction enabled a concise, four-step, stereoselective synthesis of highly functionalized 3,3-difluoro-4-pyrazolo-piperidine GSK3901383A, a key intermediate for the synthesis of a leucine-rich repeat kinase 2 inhibitor API. Computational analysis provided insight into the steric requirements of the catalytic system, enabling rational selection of a highly selective catalyst.

Silapillar[n]arenes: Their Enhanced Electronic Conjugation and Conformational Versatility.

During recent decades, methylene-bridged macrocyclic arenes have been widely used in supramolecular chemistry. However, their π-conjugations are very weak, as the methylene bridges disrupt the electronic communication between π orbitals of the aromatic units. Herein, we successfully synthesized a series of silapillar[n]arenes (n = 4, 6, and 8) using silylene bridging. These showed enhanced electronic conjugation compared with the parent pillar[n]arenes because of σ*-π* conjugation between σ* (Si-C) orbitals and π* orbitals of the benzenes. Owing to the longer Si-C bond compared with the C-C bond, silylene-bridging provides additional structural flexibility into the pillar[n]arene scaffolds; a strained silapillar[4]arene was formed, which is unavailable in the parent pillar[n]arenes because of the steric requirements. Furthermore, silapillar[n]arenes displayed interesting size-dependent structural and optical properties.

The crystal structure of SUN1-KASH6 reveals an asymmetric LINC complex architecture compatible with nuclear membrane insertion

The LINC complex transmits cytoskeletal forces into the nucleus to control the structure and movement of nuclear contents. It is formed of nuclear SUN and cytoplasmic KASH proteins, which interact within the nuclear lumen, immediately below the outer nuclear membrane. However, the symmetrical location of KASH molecules within SUN-KASH complexes in previous crystal structures has been difficult to reconcile with the steric requirements for insertion of their immediately upstream transmembrane helices into the outer nuclear membrane. Here, we report the crystal structure of the SUN-KASH complex between SUN1 and JAW1/LRMP (KASH6) in an asymmetric 9:6 configuration. This intertwined assembly involves two distinct KASH conformations such that all six KASH molecules emerge on the same molecular surface. Hence, they are ideally positioned for insertion of upstream sequences into the outer nuclear membrane. Thus, we report a SUN-KASH complex architecture that appears to be directly compatible with its biological role.

Epimerization of trans‐Cycloalkenes with the X−C=C−SeR*‐Unit – The Steric Demand of X=H, F, Cl, Br, I, Me, Et and CF3

AbstractTrans‐cycloalkenes with the X−C=C−SeR*‐unit and ring sizes from 9 to 20 have been synthesized. R* bonding the selenium atom is the chiral (S)‐o‐(1‐Methoxypropyl)phenyl‐moiety, and X=H, F, Cl, Br, I, Me, Et and CF3. The planar‐chiral trans‐cycloalkenes in combination with the chiral residue R* exist as two diastereomers. These can be distinguished in principle by NMR spectroscopy. Here, we have studied the epimerization of the trans‐cycloalkenes, i. e., the 180° rotation of the X−C=C‐unit through the cavity of the ring. The measurements were done with variable temperature 13C NMR spectroscopy within the range from −110 to 140 °C. The obtained values of the Gibbs energy of activation ΔG≠C depend strongly on the ring size. Furthermore, the ΔG≠C values show dramatic steric effects due to the groups X. The steric requirement of X increases in the series H≪F≪Cl<Me<Br<I<Et<CF3. Here, F is significantly larger than H, and CF3 is larger than Et. The corresponding iPr‐compounds could not be synthesized. The transition state structures of the ring inversion for ring sizes 8–20 were calculated at the DFT level of theory.

Interaction and Energy Decomposition Analyses to Predict Stability of Tetraaryl Square Planar Cobalt Complexes

AbstractThe sodium‐mediated cobaltation of pentafluorobenzene using the bimetallic base [NaCo(HMDS)3] (HMDS=N(SiMe3)2) has been reported to afford a novel tetraaryl Co(II) square planar complex. Yet, the preparation of analogue structures with 1,2,3,4‐tetrafluorobenzene, 1,3,5‐trichlorobenzene, and 1,4‐dibromo‐2,5‐difluorobenzene remains elusive. While the metalation step proceeds leading to stable [NaCo(HMDS)2Ar] species, the ligand redistribution process to afford the tetraaryl Co(II) square planar complexes does not take place. Herein we report a density functional theory study in combination with electronic structure and energy decomposition analyses to shed light on the electronic and steric requirements to afford such complexes. Our findings show that the formation of the Co(II) square planar complexes depends on the right balance between intramolecular X⋅⋅⋅X and Na⋅⋅⋅X (X=H, F, Cl, Br) interactions. The latter further induces a ‘seesaw effect’, whereby the aryl ligand acts as a ‘seesaw’ allowing two X atoms in ortho positions to interdependently interact with Na. Only by considering both attractive and repulsive Na(X)⋅⋅⋅X interactions, the correct stability of the square planar complexes observed in experiments can be predicted computationally. We envision these insights to guide the rational design of novel square planar metal complexes for C−C coupling, a field that is still dominated by scarce and expensive precious metals.

Acyclic diaminocarbenes (ADCs) and their catalytic activity in metal catalysed organic transformation reactions

Abstract Acyclic diaminocarbenes (ADCs)–Metal complex having strong donor ability and thermal stability led to extensive usability across every area of inorganic and organometallic chemistry. The unique properties of acyclic diaminocarbenes (ADCs) provide certain advantages over other carbene ligands and have the potential to make a great impact in catalysis. Further, the straightforward synthesis of M–ADCs (metal bound acyclic diaminocarbenes) complexes via metal-mediated reaction provides a wide range of well-defined metal carbene catalysts, which might inspire more researchers to devise unsymmetrically substituted, chiral, and novel acyclic carbene compounds. Although the above synthetic route is limited to a few late transition metals, but have great opportunities to expand the scope of this method. The application of M–ADCs complexes as a catalyst for several organic transformation reactions such as various cross-coupling reactions and asymmetric synthesis like hydroarylation, hydroazidation, hydroamination, cyclization and addition reactions which have shown comparable or even higher activities than the analogous M–NHCs based on all the reports presented. Recent findings of donor ability of several ADC ligands would be useful in fine-tuning the electronic properties, and then a catalyst with a certain combination of donicity and steric requirement could open new doors in catalytic reactivity. Thus, the objective of this review is to assess the recent growths that have been made in designing novel and chiral ADCs ligands and synthesizing ADCs–Metal complexes and to highlight catalytic activities of metal acyclic diaminocarbene complexes for cross-coupling reactions.

Group IV Complexes with Sterically Congested N-Aryl-adamantylcarbamidate Ligands.

Metalation of N-(2,6-dibenzhydryl-4-tolyl)adamantane-1-carboxamide (1, Ar*N(H)-C(O)-Ad) with M(NMe2)4 (M = Ti, Zr, Hf) yields amidate complexes Ar*N=C(Ad)-O-Ti(NMe2)3 (2) as well as bis(amidate) compounds (Ar*N=C(Ad)-O)2M(NMe2)2 (M = Zr (3), Hf (4)). In 2, the amidate ligand acts as a monodentate base via the oxygen atom with the Ti center in a slightly distorted tetrahedral environment. The steric requirement of the amidate ligand stabilizes the small coordination number of four of the Ti atom. In congeners 3 and 4, two bidentate amidate ligands exist in the coordination spheres, leading to hexacoordinate group IV metal atoms. The small bite angles of the Zr- and Hf-bound amidate ligands lead to severe distortion of the octahedral environments of the Zr and Hf centers. Titanium compound 2 is an unsuitable choice to catalyze hydrofunctionalization of alkynes with amines and phosphane oxides and despite the significantly smaller pKa value of the carboxylic amide, formation of carboxamide 1 is the dominant reaction upon addition of amines or phosphane oxides to release intramolecular steric strain introduced by the very bulky adamantylamidato ligand.

The Evolution of Phosphite‐Oxazoline Ligands for the Pd‐Allylic Substitution and Their Application in Building Chiral Molecules

AbstractPd‐catalyzed asymmetric allylic substitution (AAS) is a highly effective method for producing chiral molecules with alkene‐substituted frameworks which can be further derivatized. However, its stereochemical outcome is affected by the steric requirements of the substrate and only a narrow set of nucleophiles yield excellent enantioselectivities. In this regard, phosphite‐oxazolines have emerged as strong candidates to be privileged ligands for this process, providing results that surpass most of the previously published studies. They have provided high enantiocontrol when used in the Pd‐AAS of several hindered and unhindered substrates, using a wide range of C‐, O‐, and N‐nucleophiles. In this concept, we review and discuss the current progress made in the design of tailor‐made phosphite‐oxazoline ligand libraries for the Pd‐AAS of a broad range of substrates and nucleophiles and its application in the construction of chiral complex molecules.

Synthesis, characterization, and catalytic evaluation of palladium PEPPSI complexes bearing unsymmetrical NHC ligands in Suzuki–Miyaura reactions

Seven unsymmetrical imidazolium chlorides featuring a mesityl (Mes) or 2,6-diisopropylphenyl substituent (Dip) on one of their nitrogen atoms and a cycloalkyl group of variable size (cyclopentyl, cyclohexyl, 1-adamantanyl, cycloheptyl, cyclooctyl, or cyclododecyl) on the other one served to prepare a small library of novel palladium PEPPSI complexes with the generic formula [PdCl2(NHC)(Py)]. Three symmetrical compounds featuring the bulky yet flexible 1,3-dicyclododecylimidazol-2-ylidene and the archetypical IMes and IDip ligands were also synthesized. All the products were isolated in modest to satisfactory yields (15–85%) and fully characterized using 1H and 13C NMR spectroscopies. The molecular structures of five of them were determined using single crystal X-ray diffraction analysis, which revealed that, in most cases, the conformational freedom of the N-cycloalkyl moieties subsisted in the crystal phase. Topographic maps and %VBur parameters were computed to quantify the steric requirements of the uNHC ligands. The catalytic activity of the ten complexes was assessed in the Suzuki–Miyaura cross-coupling of phenylboronic acid and aryl halides. The reactions required only a low catalyst loading (0.05–0.25 mol%) and were carried out under mild aerobic conditions in a green, water-based solvent mixture. High yields of biphenyl derivatives were achieved with all the aryl bromides tested, irrespective of the presence of electron-donating or withdrawing substituents on their aromatic ring. When 4-chloro-acetophenone, a representative electron-poor aryl chloride served as substrate, all the complexes featuring cycloalkyl substituents on their NHC ligand became mostly inactive, whereas the IMes and IDip-based catalyst precursors maintained a high activity.

Solvation free energy arithmetic for small organic molecules.

Solvent-mediated interactions contribute to ligand binding affinities in computational drug design and provide a challenge for theoretical predictions. In this study, we analyze the solvation free energy of benzene derivatives in water to guide the development of predictive models for solvation free energies and solvent-mediated interactions. We use a spatially resolved analysis of local solvation free energy contributions and define solvation free energy arithmetic, which enable us to construct additive models to describe the solvation of complex compounds. The substituents analyzed in this study are carboxyl and nitro-groups due to their similar sterical requirements but distinct interactions with water. We find that nonadditive solvation free energy contributions are primarily attributed to electrostatics, which are qualitatively reproduced with computationally efficient continuum models. This suggests a promising route for the development of efficient and accurate models for the solvation of complex molecules with varying substitution patterns using solvation arithmetic.

Identifying novel and potent inhibitors of EGFR protein for the drug development against the breast cancer

The epidermal growth factor receptor (EGFR) has been shown to be extremely important in numerous signaling pathways, particularly those involved in cancer progression. Many therapeutic inhibitors, consisting of both small molecules and monoclonal antibodies, have been developed to target inflammatory, triple-negative and metastatic breast cancer. With the emergence of resistance in breast cancer treatment strategies, there is a need to develop novel drug targets that not only overcome resistance, but also exhibit low toxicity and high specificity. The work presented here focuses on the identification of new inhibitors against the EGFR protein using combined computational approaches. Using a comprehensive machine learning-based virtual screening approach complemented by other computational approaches, we identified six new molecules from the ZINC database. The gold docking score of these six novel molecules is 125.95, 125.38, 123.13, 119.71, 115.64 and 113.73, respectively, while the gold score of the control group is 120.74. In addition, we also analyzed the FEC value of these compounds and found that the values of compounds 1, 2, 3 and 4 (−61.82, −63.98, −67.98 and −63.32, respectively) were higher are than those of the control group (−61.05). Furthermore, these molecules showed highly stable RMSD plots and good interaction of hydrogen bonds. The identified inhibitors provided interesting insights for understanding the electronic, hydrophobic, steric and structural requirements for EGFR inhibitory activity. Distinguishing these novel molecules could lead to the development of new drugs useful in treating breast cancer.Communicated by Ramaswamy H. Sarma

Site-Specific Phosphorylation of RTK KIT Kinase Insert Domain: Interactome Landscape Perspectives

The kinase insert domain (KID) of RTK KIT is a key recruitment region for downstream signalling proteins (DSPs). KID, as a multisite phosphorylation region, provides alternative recognition sites for DSPs and activates them by binding a phosphotyrosine (pY) to their SH2 domains. Significant steric, biochemical, and biophysical requirements must be fulfilled by each pair of interacting proteins as the adaptation of their configurations is mandatory for the selective activation of DSPs. The accurate 3D atomistic models obtained by modelling and molecular dynamics (MD) simulations of phosphorylated KID (p-KID) have been delivered to describe KID INTERACTOME. By taking phosphorylated KIDpY721 and the N-terminal SH2 domain of phosphatidylinositol 3-kinase (PI3K), a physiological partner of KID, we showed the two proteins are intrinsically disordered. Using 3D models of both proteins, we probe alternative orientations of KIDpY721 relative to the SH2 binding pocket using automatic docking (HADDOCK) and intuitive user-guided docking. This modelling yields to two possible models of the functionally related non-covalent complex KIDpY721/SH2, where one can be regarded as the first precursor to probe PI3K activation via KIT KID. We suggest that such generation of a KID/SH2 complex is best suited for future studies of the post-transduction effects of RTK KIT.

Stereochemistry of low-spin cobalt porphyrins. 9. Molecular stereochemistry of two picket fence cobalt(II) derivatives

The preparation and molecular structures of two five-coordinate cobalt(II) picket fence porphyrinates with imidazole ligands are described, [Co(TpivPP)(L)] (TpivPP, dianion of picket fence porphyrin). The ligands are the unhindered imidazole, 1-ethylimidazole, and the sterically hindered imidazole, 1,2-dimethylimidazole. Although the equatorial aspects of the geometry are quite equivalent, the axial coordination group geometry strongly reflects the differing steric requirements of the axial ligand. The hindering methyl group in 1,2-dimethylimidazole, adjacent to the coordinated imidazole nitrogen atom, leads to an increased CoNIm bond distance, a tilt of the CoN bond and unequal CoNCIm bond angles, all of which serve to reduce the steric strain when compared with the unhindered derivative.