Showing papers on "Steric effects published in 2017"
TL;DR: The use of different methods to quantify and explore the steric impact of N-heterocyclic carbene (NHC) ligands are presented, including the percent buried volume (%Vbur) and steric maps, which provide a graphical representation of the sterIC profile of a ligand using colour-coded contour maps.
221 citations
TL;DR: The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni and suggest that two classic descriptors for ligand steric environment-cone angle and % buried volume-are not equivalent, despite their treatment in the literature.
Abstract: The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment-cone angle and % buried volume-are not equivalent, despite their treatment in the literature.
155 citations
TL;DR: The insights gained are transposable to other group 9 transition metals and pave the way toward rational design of C-H functionalization catalysts.
Abstract: CpXRh(III)-catalyzed C–H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (CpX) ligand structure on reaction rate and selectivity has been viewed as a black box, and a truly systematic study is lacking. Consequently, predicting the outcomes of these reactions is challenging because subtle variations in ligand structure can cause notable changes in reaction behavior. A predictive tool is, nonetheless, of considerable value to the community as it would greatly accelerate reaction development. Designing a data set in which the steric and electronic properties of the CpXRh(III) catalysts were systematically varied allowed us to apply multivariate linear regression algorithms to establish correlations between these catalyst-based descriptors and the regio-, diastereoselectivity, and rate of model reactions. This, in turn, led to the development of quantitative predictive models that describe catalyst perfo...
144 citations
TL;DR: A general method is reported that allows for an a priori predictable chemoselective Csp2 −Csp2 coupling at C−Br in preference to C−OTf and C−Cl bonds, regardless of the electronic or steric bias of the substrate.
Abstract: While chemoselectivities in Pd0-catalyzed coupling reactions are frequently non-intuitive and a result of a complex interplay of ligand/catalyst, substrate, and reaction conditions, we herein report a general method based on PdI that allows for an a priori predictable chemoselective Csp2 −Csp2 coupling at C−Br in preference to C−OTf and C−Cl bonds, regardless of the electronic or steric bias of the substrate. The C−C bond formations are extremely rapid (<5 min at RT) and are catalyzed by an air- and moisture-stable PdI dimer under open-flask conditions.
95 citations
TL;DR: This Forum Article describes the recent progress on the charge-transfer emitting triarylborane π-electron systems with novel geometries, which include the lateral boryl-substituted ρ-system with amino groups at the terminal positions, the o,o'-subst ituted biaryl ς-system, and a triaryl Borane-based BODIPY system.
Abstract: Triarylboranes have attracted significantly increasing research interest as a remarkable class of photoelectronic π-electron materials. Because of the presence of vacant p orbital on the B center, the boryl group is a very unique electron acceptor that exhibits not only electron-accepting ability through p−π* conjugation but also high Lewis acidity to coordinate with Lewis bases and steric bulk arising from the aryl substituent on the B center to get enough kinetic stability. Thus, the incorporation of a trivalent B element into π-conjugated systems is an efficient strategy to tune the electronic and stereo structures and thus the photoelectronic properties of π-electron systems. When an electron-donating group, such as amino, is present, triarylboranes would likely display intramolecular charge-transfer transitions. These kinds of molecules are often highly emissive. In addition, the geometry of the molecules has a great impact on the emission properties. In this Forum Article, we herein describe our rec...
94 citations
TL;DR: Two novel frustrated Lewis pair aminoboranes were synthesized, and their structural features were elucidated both in solution and in the solid state, and it was shown that 2 and 3 are more active catalysts for the borylation of heteroarenes than the bulkier analogue 1.
Abstract: Two novel frustrated Lewis pair (FLP) aminoboranes, (1-Pip-2-BH2-C6H4)2 (2; Pip = piperidyl) and (1-NEt2-2-BH2-C6H4)2 (3; NEt2 = diethylamino), were synthesized, and their structural features were elucidated both in solution and in the solid state. The reactivity of these species for the borylation of heteroarenes was investigated and compared to previously reported (1-TMP-2-BH2-C6H4)2 (1; TMP = tetramethylpiperidyl) and (1-NMe2-2-BH2-C6H4)2 (4; NMe2 = dimethylamino). It was shown that 2 and 3 are more active catalysts for the borylation of heteroarenes than the bulkier analogue 1. Kinetic studies and density functional theory calculations were performed with 1 and 2 to ascertain the influence of the amino group of this FLP-catalyzed transformation. The C–H activation step was found to be more facile with smaller amines at the expense of a more difficult dissociation of the dimeric species. The bench-stable fluoroborate salts of all catalysts (1F–4F) have been synthesized and tested for the borylation rea...
88 citations
TL;DR: It is demonstrated that a phosphonate metal–organic framework (MOF) platform is robust enough to accommodate up to 16 different metal clusters, allowing for systematic tuning of Lewis acidity, catalytic activity and enantioselectivity.
Abstract: Heterogeneous catalysts typically lack the specific steric control and rational electronic tuning required for precise asymmetric catalysis. Here we demonstrate that a phosphonate metal–organic framework (MOF) platform that is robust enough to accommodate up to 16 different metal clusters, allowing for systematic tuning of Lewis acidity, catalytic activity and enantioselectivity. A total of 16 chiral porous MOFs, with the framework formula [M3
L
2(solvent)2] that have the same channel structures but different surface-isolated Lewis acid metal sites, are prepared from a single phosphono-carboxylate ligand of 1,1′-biphenol and 16 different metal ions. The phosphonate MOFs possessing tert-butyl-coated channels exhibited high thermal stability and good tolerances to boiling water, weak acid and base. The MOFs provide a versatile family of heterogeneous catalysts for asymmetric allylboration, propargylation, Friedel–Crafts alkylation and sulfoxidation with good to high enantioselectivity. In contrast, the homogeneous catalyst systems cannot catalyze the test reactions enantioselectively. Asymmetric synthesis predominantly falls within the realm of homogeneous catalysis. Here, the authors synthesized 16 chiral metal–organic frameworks differing in the nature of the transition metal and demonstrate their excellent stability, catalytic activity and recyclability in a number of enantioselective reactions.
87 citations
TL;DR: The first example of a general Pd-catalyzed Suzuki-Miyaura cross-coupling of planar amides enabled by the combination of electronic-activation of the amide nitrogen in N-acylpyrroles and pyrazoles is reported.
83 citations
TL;DR: The structure and dynamics of enigmatic hexa(3,5-di-tert-butylphenyl)ethane was characterized via NMR spectroscopy for the first time.
Abstract: The structure and dynamics of enigmatic hexa(3,5-di-tert-butylphenyl)ethane was characterized via NMR spectroscopy for the first time. Our variable temperature NMR analysis demonstrates an enthalpy–entropy compensation that results in a vanishingly low dissociation energy (ΔG298d = −1.60(6) kcal mol−1). An in silico study of increasingly larger all-meta alkyl substituted hexaphenylethane derivatives (Me, iPr, tBu, Cy, 1-Ad) reveals a non-intuitive correlation between increased dimer stability with increasing steric crowding. This stabilization originates from London dispersion as expressed through the increasing polarizability of the alkyl substituents. Substitution with conformationally flexible hydrocarbon moieties, e.g., cyclohexyl, introduces large unfavourable entropy contributions. Therefore, using rigid alkyl groups like tert-butyl or adamantyl as dispersion energy donors (DED) is essential to help stabilize extraordinary bonding situations.
83 citations
TL;DR: A fully macromolecular FLP, built from linear copolymers that containing either a sterically encumbered Lewis base or Lewis acid as a pendant functional group, is reported, which is dynamic, can self-heal, is heat responsive, and can be reshaped by postgelation processing.
Abstract: Steric bulk prevents the formation of strong bonds between Lewis acids and bases in frustrated Lewis pairs (FLPs), where latent reactivity makes these reagents transformative in small molecule activations and metal-free catalysis. However, their use as a platform for developing materials chemistry is unexplored. Here we report a fully macromolecular FLP, built from linear copolymers that containing either a sterically encumbered Lewis base or Lewis acid as a pendant functional group. The target functional copolymers were prepared by a controlled radical copolymerization of styrene with designer boron or phosphorus containing monomers. Mixtures of the B- and P-functionalized polystyrenes do not react, with the steric bulk of the functional monomers preventing the favorable Lewis acid base interaction. Addition of a small molecule (diethyl azodicarboxylate) promotes rapid network formation, cross-linking the reactive polymer chains. The resulting gel is dynamic, can self-heal, is heat responsive, and can be...
80 citations
TL;DR: The results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and it is hoped that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.
Abstract: Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5'-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.
TL;DR: The domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T) method is used in conjunction with the recently introduced local energy decomposition (LED) analysis to obtain state-of-the-art dissociation energies and a clear-cut definition of the London dispersion component of the interaction.
Abstract: The interaction of Lewis acids and bases in both classical Lewis adducts and frustrated Lewis pairs (FLPs) is investigated to elucidate the role that London dispersion plays in different situations. The analysis comprises 14 different adducts between tris(pentafluorophenyl)borane and a series of phosphines, carbenes, and amines with various substituents, differing in both steric and electronic properties. The domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) method is used in conjunction with the recently introduced local energy decomposition (LED) analysis to obtain state-of-the-art dissociation energies and, at the same time, a clear-cut definition of the London dispersion component of the interaction, with the ultimate goal of aiding in the development of designing principles for acid/base pairs with well-defined bonding features and reactivity. In agreement with previous DFT investigations, it is found that the London dispersion dominates the interaction energy in FLPs, and is also remarkably strong in Lewis adducts. In these latter systems, its magnitude can be easily modulated by modifying the polarizability of the substituents on the basic center, which is consistent with the recently introduced concept of dispersion energy donors. By counteracting the destabilizing energy contribution associated with the deformation of the monomers, the London dispersion drives the stability of many Lewis adducts.
TL;DR: It is led to the conclusion that, while an all-inclusive definition of FLP is challenging, the notion of ‘FLP chemistry’ is more readily recognized.
Abstract: In this concept article, we consider the notion of frustrated Lewis pairs (FLPs). While the original use of the term referred to steric inhibition of dative bond formation in a Lewis pair, work in ...
TL;DR: A method for enantioselective direct α-amination reaction catalyzed by a sterically "frustrated" Lewis acid/Brønsted base complex is disclosed and delivers α-aminocarbonyl compounds in high enantiomeric purity.
Abstract: A method for enantioselective direct α-amination reaction catalyzed by a sterically “frustrated” Lewis acid/Bronsted base complex is disclosed. Cooperative functioning of the Lewis acid and Bronsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond activated dialkyl azodicarboxylates delivers α-aminocarbonyl compounds in high enantiomeric purity.
TL;DR: The authors show the unusual functionalization of α-ethereal C–H bonds mediated by singlet oxygen under mild conditions to afford lactones and hydroperoxide products.
Abstract: Singlet O2 is a key reactive oxygen species responsible for photodynamic therapy and is generally recognized to be chemically reactive towards C=C double bonds. Herein, we report the hydroperoxidation/lactonization of α-ethereal C–H bonds by singlet O2 (1Δg) under exceptionally mild conditions, i.e., room temperature and ambient pressure, with modest to high yields (38~90%) and excellent site selectivity. Singlet O2 has been known for > 90 years, but was never reported to be able to react with weakly activated C–H bonds in saturated hydrocarbons. Theoretical calculations indicate that singlet O2 directly inserts into the α-ethereal C–H bond in one step with conservation of steric configuration in products. The current discovery of chemical reaction of singlet oxygen with weakly activated solvent C–H bonds, in addition to physical relaxation pathway, provides an important clue to a 35-year-old unresolved mystery regarding huge variations of solvent dependent lifetime of singlet O2. Singlet oxygen is known to react with carbon–carbon double bonds. Here, the authors show the unusual functionalization of α-ethereal C–H bonds mediated by singlet oxygen under mild conditions to afford lactones and hydroperoxide products.
TL;DR: Porous polymer networks based on sterically encumbered triphenylphosphine motifs, mimicking the basic sites employed in frustrated Lewis pair (FLP) chemistry, were synthesized via Yamamoto polymerization and their interactions with the strong Lewis acid B(C6F5)3 probed.
Abstract: Porous polymer networks based on sterically encumbered triphenylphosphine motifs, mimicking the basic sites employed in frustrated Lewis pair (FLP) chemistry, were synthesized via Yamamoto polymerization and their interactions with the strong Lewis acid B(C6F5)3 probed. The combinations yield semi-immobilized FLPs, which are able to cleave dihydrogen heterolytically at ambient temperature and low hydrogen pressure.
TL;DR: The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented, and this metal-free catalytic variant displays a notably broad chemoselectivity and generality.
Abstract: The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.
TL;DR: This type of Pd-PEPPSI precatalyst showed the most efficiency reported to date for the challenging C-N cross-coupling reactions requiring no anhydrous and inert atmosphere protections, suggesting flexible steric bulk as a promising catalyst design strategy.
Abstract: To achieve efficient palladium-catalyzed cross-coupling reaction under mild reaction conditions with the flexible steric bulk strategy, a series of Pd-PEPPSI (PEPPSI: pyridine-enhanced precatalyst preparation, stabilization, and initiation) complexes C1–C6 were synthesized and characterized, in which unsymmetric flexible steric bulk was introduced on the N-aryl of ancenaphthyl skeleton. These well-defined palladium complexes were found to be excellent precatalysts for Buchwald–Hartwig amination of aryl chlorides with amines in air. The electronic effect of the Pd-PEPPSI complexes and the effect of ancillary pyridine ligands were evaluated, among which complex C3 exhibited the most efficiency. It was demonstrated that the cross-coupling products were obtained in excellent yields in the presence of 0.5–0.1 mol % palladium loading. A wide range of aryl- and heteroaryl chlorides as well as various amines were compatible. The oxidative addition of aryl chlorides is revealed to be the rate-determining step in t...
TL;DR: The rarely used boron Lewis acid tris[3,5-bis(trifluoromethyl)phenyl]borane (BArF3) is found to be an excellent catalyst for metal-free hydroboration of imines as mentioned in this paper.
TL;DR: Using this correlation, the integration of simple linear regressions with gold(I) catalysis to interrogate the influence of phosphine structure on metal-catalyzed organic transformations was able to accurately predict the selectivity of a previously untested, Buchwald-type ligand to enhance selectivity for the same transformation.
Abstract: Herein, we report the integration of simple linear regressions with gold(I) catalysis to interrogate the influence of phosphine structure on metal-catalyzed organic transformations. We demonstrate that observed product ratios in [4 + 3]/[4 + 2] cycloisomerization processes are influenced by both steric and electronic properties of the phosphine, which can be represented by the Au–Cl distance. In contrast, the observed selectivity of a similar [2 + 3]/[2 + 2] cycloisomerization is governed by L/B1, a steric parameter. Using this correlation, we were able to accurately predict the selectivity of a previously untested, Buchwald-type ligand to enhance selectivity for the same transformation. This ligand found further utility in increasing the selectivity of a previously reported gold-catalyzed cycloisomerization/arylation of 1,6-enynes by ∼1 kcal/mol.
TL;DR: Structural and theoretical analysis of silanones 2 indicate a short Si=O bond and an enhanced polarization toward the O atom compared to Me2Si=O owing to the strong π-electron donation from the phosphonium ylide substituent.
Abstract: Silanones substituted by bulky amino- and phosphonium ylide substituents have been synthesized and isolated in crystalline form. Thanks to the steric protection and the strong electron-donating ability of substituents, silanones 2 are persistent and only slowly dimerizes at room temperature (t1/2 = 0.5 or 5 h). Structural and theoretical analysis of the silanone indicate a short Si=O bond (1.533 A) and an enhanced polarization toward O atom compared to Me2Si=O due to the strong pi-electron donation from the phosphonium ylide substituent.
TL;DR: The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron-withdrawing activating groups, and provides a method for n→n+4 ring expansion.
Abstract: Analogues of dibenzodiazepines, in which the seven-membered nitrogen heterocycle is replaced by a 9–12-membered ring, were made by an unactivated Smiles rearrangement of five- to eight-membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron-withdrawing activating groups, and provides a method for n→n+4 ring expansion. The medium-ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.
TL;DR: 4,7-Bis-[3-(dimesitylboryl)thien-2-yl]benzothiadiazole and monoborylated derivative 2 were synthesized and their chromic behavior was investigated, revealing an intramolecular B-N coordination bond formed reversibly.
Abstract: 4,7-Bis-[3-(dimesitylboryl)thien-2-yl]benzothiadiazole (1) and monoborylated derivative 2 were synthesized and their chromic behavior was investigated. Photophysical measurements, single-crystal XRD analysis, and theoretical calculations revealed that an intramolecular B−N coordination bond formed reversibly. The equilibrium of this reversible bond formation depends on the solid-state structure, solvent, temperature, and mechanical forces, and leads to significant changes in the electronic structure and chromic behavior of these molecules. The responsiveness toward external stimuli, resulting in the reversible formation of open and closed forms of this system, is achieved through weak intramolecular B−N coordination bonds induced by the steric bulk of the mesityl groups on the boron centers.
TL;DR: The catalytic, enantioselective, cyclization of phenols with electrophilic sulfenophthalimides onto isolated or conjugated alkenes affords 2,3-disubstituted benzopyrans and benzoxepins and an improved method for the selective C(2) allylation of Phenols is described.
Abstract: The catalytic, enantioselective, cyclization of phenols with electrophilic sulfenophthalimides onto isolated or conjugated alkenes affords 2,3-disubstituted benzopyrans and benzoxepins. The reaction is catalyzed by a BINAM-based phosphoramide Lewis base catalyst which assists in the highly enantioselective formation of a thiiranium ion intermediate. The influence of nucleophile electron density, alkene substitution pattern, tether length and Lewis base functional groups on the rate, enantio- and site-selectivity for the cyclization is investigated. The reaction is not affected by the presence of substituents on the phenol ring. In contrast, substitutions around the alkene strongly affect the reaction outcome. Sequential lengthening of the tether results in decreased reactivity, which necessitated increased temperatures for reaction to occur. Sterically bulky aryl groups on the sulfenyl moiety prevented erosion of enantiomeric composition at these elevated temperatures. Alcohols and carboxylic acids prefer...
TL;DR: In this article, a density functional theory with numerical atomic functions was used to predict the fine structures of Mo-E, Mo-X, Co-Mixed Mo-edge (Mo-X), Co-E and Corner sites.
TL;DR: An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed, which gives rise to in situ enolate generation from monocarbonyl compounds.
Abstract: An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Bronsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Bronsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond-activated aldimines delivers β-aminocarbonyl compounds with high enantiomeric purity.
TL;DR: The results imply a synchronous concerted mechanism, in which the proton and electron transfer components of the CPET process make equal contributions to the rate constants.
Abstract: Multiple-site concerted proton-electron transfer (MS-CPET) reactions were studied in a three-component system. 1-Hydroxy-2,2,6,6-tetramethylpiperidine (TEMPOH) was oxidized to the stable radical TEMPO by electron transfer to ferrocenium oxidants coupled to proton transfer to various pyridine bases. These MS-CPET reactions contrast with the usual reactivity of TEMPOH by hydrogen atom transfer (HAT) to a single e-/H+ acceptor. The three-component reactions proceed by pre-equilibrium formation of a hydrogen-bonded adduct between TEMPOH and the pyridine base, and the adduct is then oxidized by the ferrocenium in a bimolecular MS-CPET step. The second-order rate constants, measured using stopped-flow kinetic techniques, spanned 4 orders of magnitude. An advantage of this system is that the MS-CPET driving force could be independently varied by changing either the pKa of the base or the reduction potential (E°) of the oxidant. Changes in ΔG°MS-CPET from either source had the same effect on the MS-CPET rate constants, and a combined Bronsted plot of ln(kMS-CPET) vs ln(Keq) was linear with a slope of 0.46. These results imply a synchronous concerted mechanism, in which the proton and electron transfer components of the CPET process make equal contributions to the rate constants. The only outliers to the Bronsted correlation are the reactions with sterically hindered pyridines, which apparently hinder the close approach of proton donor and acceptor that facilitates MS-CPET. These three-component reactions are compared with a related HAT reaction of TEMPOH, with the 2,4,6-tri-tert-butylphenoxyl radical. The MS-CPET and HAT oxidations of TEMPOH at the same driving force occurred with similar rate constants. While this is an imperfect comparison, the data suggest that the separation of the proton and electron to different reagents does not significantly inhibit the proton-coupled electron transfer process.
TL;DR: The origin of asymmetric induction in the addition of carbon and nitrogen-centered radicals to octahedral centrochiral rhodium enolates has been investigated with density functional theory calculations.
Abstract: The origin of asymmetric induction in the additions of carbon- and nitrogen-centered radicals to octahedral centrochiral rhodium enolates has been investigated with density functional theory calculations. Computed free energies of activation reproduce the preference for the experimentally observed major enantiomer. Good levels of enantioselectivity are maintained upon replacement of the bulky tert-butyl substituents on the ligands with methyl groups. Distortion-interaction analysis indicates that for both carbon- and nitrogen-centered radicals, which have relatively early and late transition states, respectively, the difference in the distortion energies controls the enantioselectivity. In the enolate derived from the Λ-configured catalyst, the tert-butyl group that shields the si face of the substrate plays the most sterically significant steric role by directly hindering access to the enolate double bond. Exploration of the effect of the N substituent size and shape on the imidazole substrate shows that...
TL;DR: The selective C-H carbonylation of methylene bonds, in the presence of traditionally more reactive methyl C–H and C(sp2)–H bonds,In α-tertiary amines is reported.
Abstract: The selective C–H carbonylation of methylene bonds in the presence of traditionally more reactive methyl C–H and C(sp2)–H bonds in α-tertiary amines is reported. The exceptional selectivity is driven by the bulky α-tertiary amine motif, which we hypothesise orientates the activating C–H bond proximal to Pd in order to avoid an unfavourable steric clash with a second α-tertiary amine on the Pd centre, promoting preferential cyclopalladation at the methylene position. The reaction tolerates a range of structurally interesting and synthetically versatile functional groups, delivering the corresponding β-lactam products in good to excellent yields.
TL;DR: The great sensitivity of this model allowed us to show unambiguously that a methyl appears bigger than a chlorine and gave the following order in size: CN > OMe > OH.
Abstract: A steric scale of 20 recurrent groups was established from comparison of rotational barriers on N-(o-substituted aryl)thiazoline-2-thione atropisomers. The resulting energy of activation ΔG⧧rot reflects the spatial requirement of the ortho substituent borne by the aryl moiety, electronic aspects and external parameters (temperature and solvent) generating negligible contributions. Concerning divergent rankings reported in the literature, the great sensitivity of this model allowed us to show unambiguously that a methyl appears bigger than a chlorine and gave the following order in size: CN > OMe > OH. For the very bulky CF3 and iPr groups, constraints in the ground state decreased the expected ΔG⧧rot values resulting in a minimization of their apparent sizes.