Search

A new strategy to stabilize free radicals electronically is described by conjugating formally antiaromatic substituents to the free radical. With an antiaromatic substituent, the radical acts as an electron sink to allow configuration mixing of a low-energy zwitterionic state that provides antiaromaticity relief to the substituent. A combination of X-ray crystallography, VT-EPR and VT-UV/Vis spectroscopy, as well as computational analysis, was used to investigate this phenomenon. We find that this strategy of antiaromaticity relief is successful at stabilizing radicals, but only if the antiaromatic substituent is constrained to be planar by synthetically imposed conformational restraints that enable state mixing. This work leads to the counterintuitive finding that increasing the antiaromaticity of the radical substituent leads to greater radical stability, providing proof of concept for a new stereoelectronic approach for stabilizing free radicals.

The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX → π*C═O interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX → π*C═O interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-C═O interactions are through the nO → π*C═O electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.

Charge transport in a single-molecule junction is extraordinarily sensitive to both the internal electronic structure of a molecule and its microscopic environment. Two distinct conductance states of a prototype terphenyl molecule are observed, which correspond to the bistability of outer phenyl rings at each end. An azobenzene unit is intentionally introduced through atomically precise side-functionalization at the central ring of the terphenyl, which is reversibly isomerized between trans and cis forms by either electric or optical stimuli. Both experiment and theory demonstrate that the azobenzene side-group delicately modulates charge transport in the backbone via a single-molecule stereoelectronic effect. We reveal that the dihedral angle between the central and outer phenyl ring, as well as the corresponding rotation barrier, is subtly controlled by isomerization, while the behaviors of the phenyl ring away from the azobenzene are hardly affected. This tunability offers a new route to precisely engineer multiconfigurational single-molecule memories, switches, and sensors.

Stereoelectronic effects are crucial in governing the conformational behaviour of small molecules bearing heterocyclic rings adjacent to amides. It dictates the antagonist and agonist activity for G-protein coupled receptor (C3aR) of inflammatory protein complement C3a on human macrophages. We have examined the role of non-covalent attractive interactions of heteroatoms of heterocycles adjacent to amides in the antagonists of C3a receptor (C3aR) using the CBS-QB3 and M06-2X/aug-cc-pVDZ levels of theory. The contribution of orbital interaction (n → σ* delocalization) towards the stability of antagonist has been examined and the systems were designed for the clear preference of such molecules to bind with C3aR protein. The molecular electrostatic potential (MESP) analysis also revealed the presence of Sigma-holes (σ-holes) in such systems interacting with the amide oxygen and contributed to the stability of the cis-conformation responsible for the antagonist behavior of such molecules. The –CF3 substituted electron-withdrawing group attached to the carbon atom of the –C–X bond enhanced the attractive non-covalent interaction between X(heterocycle) and O(amide) and electrostatic interactions that contribute to the stability of the cis-conformation of the antagonists. The –CF3 substituted selenazole ring (6Se-a) was stabilized by ∼4.0 kcal mol−1 than the other corresponding possible conformations. The non-covalent interaction (NCI) plot corroborates the non-covalent interactions between the heteroatoms in such molecules. The docking study performed with ligands L-1 and L-2 showed improved interaction with C3aR compared to those with the reported SB290157. Importantly, the cis-conformation of the ligands L-1 and L-2 persisted in the C3aR environment. The influence of the stereoelectronic effect on conformations of small ligands acting as antagonists towards G-protein coupled C3aR has been highlighted to design new candidates with better efficacy.

l-Rhamnose forms the key components of important antigenic oligo- and polysaccharides of a variety of pathogens. Obtaining 1,2-cis stereoselectivity in the glycosylation of l-rhamnoside is quite challenging due to the unavailability of neighboring group participation and disfavoring of the anomeric effect and stereoelectronic effect of the substituents on the C-2 axial position. Nevertheless, various methodologies have been developed exploiting diverse pathways for obtaining β-stereoselectivity in the glycosylation of l-rhamnose. This review describes the recent advances in β-l-rhamnosylation and its applications in the total synthesis of β-l-rhamnose-containing biologically important oligosaccharides.

How far can we push the limits in removing stereoelectronic protection from an unstable intermediate? We address this question by exploring the interplay between the primary and secondary stereoelectronic effects in the Baeyer–Villiger (BV) rearrangement by experimental and computational studies of γ-OR-substituted γ-peroxylactones, the previously elusive non-strained Criegee intermediates (CI). These new cyclic peroxides were synthesized by the peroxidation of γ-ketoesters followed by in situ cyclization using a BF3·Et2O/H2O2 system. Although the primary effect (alignment of the migrating C–Rm bond with the breaking O–O bond) is active in the 6-membered ring, weakening of the secondary effect (donation from the OR lone pair to the breaking C–Rm bond) provides sufficient kinetic stabilization to allow the formation and isolation of stable γ-hydroperoxy-γ-peroxylactones with a methyl-substituent in the C6-position. Furthermore, supplementary protection is also provided by reactant stabilization originating from two new stereoelectronic factors, both identified and quantified for the first time in the present work. First, an unexpected boat preference in the γ-hydroperoxy-γ-peroxylactones weakens the primary stereoelectronic effects and introduces a ∼2 kcal mol−1 Curtin–Hammett penalty for reacquiring the more reactive chair conformation. Second, activation of the secondary stereoelectronic effect in the TS comes with a ∼2–3 kcal mol−1 penalty for giving up the exo-anomeric stabilization in the 6-membered Criegee intermediate. Together, the three new stereoelectronic factors (inverse α-effect, misalignment of reacting bonds in the boat conformation, and the exo-anomeric effect) illustrate the richness of stereoelectronic patterns in peroxide chemistry and provide experimentally significant kinetic stabilization to this new class of bisperoxides. Furthermore, mild reduction of γ-hydroperoxy-γ-peroxylactone with Ph3P produced an isolable γ-hydroxy-γ-peroxylactone, the first example of a structurally unencumbered CI where neither the primary nor the secondary stereoelectronic effect are impeded. Although this compound is relatively unstable, it does not undergo the BV reaction and instead follows a new mode of reactivity for the CI – a ring-opening process., Protecting stereoelectronic effects prevent Baeyer–Villiger rearrangement and stabilize γ-OX-γ-peroxylactones (X = H, OH), the previously elusive non-strained Criegee intermediates.

We herein report the development of a conformationally defined, electron-rich, C2 -symmetric, P-chiral bisphosphorus ligand, ArcPhos, by taking advantage of stereoelectronic effects in ligand design. With the Rh-ArcPhos catalyst, excellent enantioselectivities and unprecedentedly high turnovers (TON up to 10 000) were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides, to generate a series of chiral cis-2-alkyl-substituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios. This method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)-tofacitinib.

We report the synthesis and biophysical evaluation of an azabicycle dinucleotide with restricted γ, β, and ε torsion angles, featuring the introduction of a piperidine ring that locks the conformation of the nucleoside into an RNA-type nucleic acid. The conceptual basis of the design is predicated upon the notion that the conformation of the phosphate group linking two RNA nucleotides can be approximated with an azabicyclic phosphoramidite which may also benefit from a unique stereoelectronic effect.

Although carbon is the central element of organic chemistry, oxygen is the central element of stereoelectronic control in organic chemistry. Generally, a molecule with a C–O bond has both a strong donor (a lone pair) and a strong acceptor (e.g., a σ*C–O orbital), a combination that provides opportunities to influence chemical transformations at both ends of the electron demand spectrum. Oxygen is a stereoelectronic chameleon that adapts to the varying situations in radical, cationic, anionic, and metal-mediated transformations. Arguably, the most historically important stereoelectronic effect is the anomeric effect (AE), i.e., the axial preference of acceptor groups at the anomeric position of sugars. Although AE is generally attributed to hyperconjugative interactions of σ-acceptors with a lone pair at oxygen (negative hyperconjugation), recent literature reports suggested alternative explanations. In this context, it is timely to evaluate the fundamental connections between the AE and a broad variety of O-functional groups. Such connections illustrate the general role of hyperconjugation with oxygen lone pairs in reactivity. Lessons from the AE can be used as the conceptual framework for organizing disjointed observations into a logical body of knowledge. In contrast, neglect of hyperconjugation can be deeply misleading as it removes the stereoelectronic cornerstone on which, as we show in this review, the chemistry of organic oxygen functionalities is largely based. As negative hyperconjugation releases the “underutilized” stereoelectronic power of unshared electrons (the lone pairs) for the stabilization of a developing positive charge, the role of orbital interactions increases when the electronic demand is high and molecules distort from their equilibrium geometries. From this perspective, hyperconjugative anomeric interactions play a unique role in guiding reaction design. In this manuscript, we discuss the reactivity of organic O-functionalities, outline variations in the possible hyperconjugative patterns, and showcase the vast implications of AE for the structure and reactivity. On our journey through a variety of O-containing organic functional groups, from textbook to exotic, we will illustrate how this knowledge can predict chemical reactivity and unlock new useful synthetic transformations.

In an effort to develop efficient Ru(II)–NHC-based catalyst considering their stereoelectronic effect for hydride-transfer reaction, we found that the ancillary NHC ligand can play a significant role in its catalytic performance. This effect is demonstrated by comparing the activity of two different types of orthometalated precatalysts of general formula [(p-cymene)(NHC)RuII(X)] (NHC = an imidazolylidene-based ImNHC, compound 2a–c, or a mesoionic triazolylidene-based tzNHC, compound 4) in transfer hydrogenation of carbonyl substrates. The electron-rich precatalyst, 2c, containing p-OMe-substituted NHC ligand performed significantly better than both unsubstituted complex 2a and p-CF3 substituted electron-poor complex 2b in ketone reduction. Whereas bulky mesoionic triazolylidene ligand containing complex 4 was found to be superior catalyst for aldehyde reduction and the precatalyst 2a is more suitable for the selective transfer hydrogenation of a wide range of aromatic aldimines to amines. To the best of o...

The UM06-2X/aug-cc-pVTZ//UM06-2X/6-311G(d) theoretical models of representative singlet trans-2′-substituted cyclobutylcarbenes were computed. The :CH-group of carbenes with an ERG is bent toward the c-C4H7-ring’s proximal C1′–C2′ single bond. The :CH-group of carbenes with an EWG is bent toward the c-C4H7-ring’s distal C1′–C4′ single bond. The contrasting stereoelectronic effect was computationally tested using trimethylsilyl vs. bromo substituents to determine if exo-1- and exo-2-substituted bicyclo[2.1.0]pentanes would be produced in diastereomeric excess.

Hemiketals are important targets for crystal prediction and molecular modeling. The supramolecular stereoelectronic effect (SSE) recently found in carboxylic acid associates occurs in hemiketals: the presence and nature of an H-bond acceptor affect the conformational preference of hemiketals. To provide a structural basis for the multitude of biological roles played by hemiketal-containing structures, it is important to accurately model their spatial and dynamic properties, so the SSE in hemiketals should be explicitly implemented in future force fields.

Cyclometalated complexes are an important class of (pre)catalysts in many reactions including hydride transfer. The ring size of such complexes could therefore be a relevant aspect to consider while modulating their catalytic activity. However, any correlation between the cyclometalating ring size and the catalytic activity should be drawn by careful assessment of the pertinent geometrical parameters, and overall electronic effects thereof. In this study, we investigated the vital role of key stereoelectronic functions of two classes of iridacyclic complexes-five-membered and six-membered cycles-in manupulating the catalytic efficiency in a model hydride-transfer reaction. Our investigation revealed that there exists an interesting multidimensional synergy among all the relevant stereoelectronic factors-yaw angle, bite angle, and the electronic properties of both the ligand and the metal center-that governs the hydride donor ability (hydricity) of the complexes during catalysis. Thus the six-membered chelate complexes with small yaw and large bite angles, strong donor ligand, and electron-rich metal were found to be better catalysts than their five-membered analogues. A frontier molecular orbital analysis supported the significant role of the above stereoelectronic synergistic effect associated with the chelate ring to control the hydride donor ability of the complexes.

The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2-allylamino)acrylic acid derivatives. Subsequent pKa studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The trans/cis amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a trans-amide is extraordinary, and in this regard, 2,4-methanoproline ...

The structures of the cocrystalline adducts of 3-nitrophenol (3-NP) with 1,3,5,7-tetraazatricyclo[3.3.1.13,7]decane [HMTA, (1)] as the 2:1:1 hydrate, 2C6H5NO3·C6H12N4·H2O, (1a), with 1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecane [TATU (2)] as the 2:1 cocrystal, 2C6H5NO3·C7H14N4, (2a), and with 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane [TATD, (3)] as the 2:1 cocrystal, 2C6H5NO3·C8H16N4, (3a), are reported. In the binary crystals (2a) and (3a), the 3-nitrophenol molecules are linked via O—H...N hydrogen bonds into aminal cage azaadamantanes. In (1a), the structure is stabilized by O—H...N and O—H...O hydrogen bonds, and generates ternary cocrystals. There are C—H...O hydrogen bonds present in all three cocrystals, and in (1a), there are also C—H...O and C—H...π interactions present. The presence of an ethylene bridge in the structures of (2) and (3) defines the formation of a hydrogen-bonded motif in the supramolecular architectures of (2a) and (3a). The differences in the C—N bond lengths of the aminal cage structures, as a result of hyperconjugative interactions and electron delocalization, were analysed. These three cocrystals were obtained by the solvent-free assisted grinding method. Crystals suitable for single-crystal X-ray diffraction were grown by slow evaporation from a mixture of hexanes.

Biphenyl, as the elementary unit of organic functional materials, has been widely used in electronic and optoelectronic devices. However, over decades little has been fundamentally understood regarding how the intramolecular conformation of biphenyl dynamically affects its transport properties at the single-molecule level. Here, we establish the stereoelectronic effect of biphenyl on its electrical conductance based on the platform of graphene-molecule single-molecule junctions, where a specifically designed hexaphenyl aromatic chain molecule is covalently sandwiched between nanogapped graphene point contacts to create stable single-molecule junctions. Both theoretical and temperature-dependent experimental results consistently demonstrate that phenyl twisting in the aromatic chain molecule produces different microstates with different degrees of conjugation, thus leading to stochastic switching between high- and low-conductance states. These investigations offer new molecular design insights into building functional single-molecule electrical devices.

The influence of diarylamino (Ar2N–) substituents on the oxidation potential of 3,7-bis(diarylamino)phenothiazines (Ar2N)2–PTZ (1a–f, a: carbazolyl; b: dihydrodibenzoazepinyl; c: dibenzoazepinyl; d: diphenylamino; e: phenothiazinyl; and f: phenoxazinyl) is investigated, where the Ar2N-substituent sequence a→f is aligned in the increasing order of their electron-donating ability. Interestingly, a different sequence of electron-donating ability for Ar2N-substituents was observed for the oxidation potentials of (Ar2N)2–PTZ: 1a (Eox1 = +0.35 V vs. Fc/Fc+) > 1f (+0.30 V) > 1e (+0.15 V) > 1d (−0.05 V) > 1c (−0.19 V) > 1b (−0.22 V). The observed sequence can be explained by the stereoelectronic effect of the Ar2N-substituents to stabilize (Ar2N)2–PTZ˙+. Clear-cut examples are observed in the crystal structure of 1c˙+ and 1e˙+, for which coplanar conformation is observed between the PTZ˙+-plane and the planes of the sp2-hybridized nitrogen atoms in Ar2N-substituents through a large conformational change during the oxidation process of (Ar2N)2–PTZ.

A novel route to functionalized [3]dendralenes with an allylsilane as integral component has been developed. The key step involves a dimethylsulfonium methylide mediated olefination of appropriately substituted silylmethylethenylidene phosphonoacetate followed by Horner–Wadsworth–Emmons reaction with aromatic aldehydes. The tri- and tetra substituted [3]dendralenes are stable towards self Diels–Alder cyclodimerization which can be attributed to stereoelectronic effect of the silylmethyl group favoring for an unreactive conformation.

The structures and energies of 1,2,7-thiadiazepane 1,1-dioxide and the axial and equatorial conformers of 1,2,7-thiadiazepane 1-oxide were calculated using the hybrid density functional B3LYP with the cc-pVDZ basis set. The results obtained explain the lower stabilities of equatorial conformers compared to the axial analogs and the lower stabilities of sulfones compared to sulfoxides.

Theoretical and analytical thermal and electrical properties are studied through the 2,7-Di([1,1&rsquo, biphenyl]-4-yl)-9H-fluorene aromatic system as a prototype of a molecular switch. Variations of the dihedral angles between the two Benzene rings at each end of the molecule have been considered, thus determining the dependence on the structural variation of the molecule when the aromatic system is connected between metal contacts. The molecule is modeled through a Tight-Binding Hamiltonian where&mdash, from the analytical process of decimation and using Green&rsquo, s functions&mdash, the probability of transmission (T) is calculated by using the Fisher&ndash, Lee relationship. Consequently, the thermal and electrical transport properties such as I &minus, V curves, quantum noise (S), Fano factor (F), electrical conductance (G), thermal conductance ( &kappa, ), Seebeck coefficient (Q), and merit number ( Z T ) are calculated. The available results offer the possibility of designing molecular devices, where the change in conductance or current induced by a stereoelectronic effect on the molecular junctions (within the aromatic system) can produce changes on the insulating&ndash, conductive states.

Achieving acyclic conformational control over several bonds has been realized by the strategic installation of a vicinal difluoroethane bridge in a generic proline-derived organocatalyst. The torsion angle ϕFCCF is governed by stabilizing hyperconjugative interactions (σ→σ*), thus ensuring a 60° relationship. This effect has been telescoped by positioning a stereogenic fluorine center proximal to the nucleophilic amine. Upon iminium formation, this center is rendered electron deficient, thus triggering a dynamic fluorine iminium ion gauche effect. Consequently, conformational control over five atoms and four bonds can be achieved by reversible formation of an iminium π-bond.

A ruthenium catalyzed intramolecular C-S coupling reaction of N-arylthioureas for the synthesis of 2-aminobenzothiazoles has been developed. Kinetic, isotope labeling, and computational studies reveal the involvement of an electrophilic ruthenation pathway instead of a direct C-H activation. Stereoelectronic effect of meta-substituents on the N-arylthiourea dictates the final regioselective outcome of the reaction.

The anomeric effect accounts for the greater thermodynamic stability of axially arranged six-membered heterocycles holding an electronegative substituent at the C1 position. Within a frame of no general consensus, two different theories are typically claimed to justify this effect mostly based on either hyperconjugative or electrostatic factors. Here we report a theoretical-experimental study of the role of both as anomeric triggers in two archetypical 1,4-dioxane derivatives, using a suitable combination of spectroscopic (IR and vibrational circular dichroism) and computational techniques for the analysis of the solvation environment effect in their anomeric choices. VCD and IR spectroscopies are used as conformer-discriminating tools: a detailed analysis of the evolution of the spectral profiles allows assessing the theoretically predicted changes in the experimental α/β ratios when changing the polar solvent, which are fully explained on the basis of an extensive NBO energy partition scheme that provides a detailed view of the role of hyperconjugative and electrostatic interactions as anomeric regulators. Our results suggest that the anomeric equilibrium cannot be described by a single stereoelectronic effect but by the combined contribution of hyperconjugation and electrostatic repulsions, so that the β-anomeric choice in polar solvents is markedly driven by the strong attenuation of electrostatic repulsive interactions that occurs in solution.

This paper reports the synthesis of a series of piperidones 1–8 by the Mannich reaction and analysis of their structures and conformations in solution by NMR and mass spectrometry. The six-membered rings in 2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-ones, compounds 1 and 2, adopt a chair–boat conformation, while those in 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ones, compounds 3–8, adopt a chair–chair conformation because of stereoelectronic effects. These stereoelectronic effects were analyzed by the 1JC–H coupling constants, which were measured in the 13C satellites of the 1H NMR spectra obtained with the hetero-dqf pulse sequence. In the solid state, these stereoelectronic effects were investigated by measurement of X-ray diffraction data, the molecular geometry (torsional bond angles and bond distances), and inter- and intramolecular interactions, and by natural bond orbital analysis, which was performed using density functional theory at the ωB97XD/6311++G(d,p) level. We found that one of the main factors influencing the conformational stability of 3–8 is the interaction between the lone-pair electrons of nitrogen and the antibonding sigma orbital of C(7)–Heq (nN→σ*C–H(7)eq), a type of hyperconjugative interaction.

Hsung et al. have reported a series of torquoselective electrocyclizations of chiral 1-azahexa-1,3,5-trienes that yield functionalized dihydropyridines. To understand the origins of the torquoselectivities of these azaelectrocyclizations, we modeled these electrocyclic ring closures using the M06-2X density functional. A new stereochemical model that rationalizes the observed 1,2 stereoinduction emerges from these computations. This model is an improvement and generalization of the “inside-alkoxy” model used to rationalize stereoselectivities of 1,3-dipolar cycloaddition of chiral allyl ethers and emphasizes a stabilizing hyperconjugative effect, which we have termed a transition state gauche effect. This stereoelectronic effect controls the conformational preferences at the electrocyclization transition states, and only in one of the allowed, disrotatory electrocyclization transition states is the ideal stereoelectronic arrangement of substituent achieved without the introduction of a steric clash. Computational experiments confirm the role of this effect as a stereodeterminant, since substrates with electropositive groups like a silyl substituent and electronegative groups have different conformational preferences at the transition state and undergo ring closure with divergent stereochemical outcomes. This predicted reversal of stereoselectivity for the ring closure of a silyl-substituted azatriene has been demonstrated experimentally.

A stereoselective N-iminium ion cyclization with allylsilane to construct vicinal quaternary-tertiary carbon centers was developed for the concise synthesis of (±)-cephalotaxine. The current strategy features a TiCl4-promoted cyclization and ring-closure metathesis to furnish the spiro-ring system. The stereochemical outcome in the N-acyliminium ion cyclization was rationalized by the stereoelectronic effect of the Z- or E-allylsilane. Two diastereomers arising from the cyclization were merged into the formal synthesis of (±)-cephalotaxine.

The anionic complex [Ir(2-phenylpyridine)2(benzene-1,2-dithiolate)](-) ([IrSS](-)) is a nucleophile and metalloligand that reacts with methyl iodide and AuPR3(+) (R = Ph or Et) to form S-methylated complexes (thiother-thiolate and dithiother complexes) and S-aurated complexes, respectively. The reactions are completely diastereselective, producing only the enantiomers ΛS and ΔR or ΛSS and ΔRR. The diastereoselectivity is stereoelectronically controlled by the orientation of the highest occupied molecular orbital (HOMO) of [IrSS](-) arising from filled dπ-pπ antibonding interactions, and the chirality of the iridium ion. Methylation or auration removes the high-energy lone pair of the thiolate S atom, leading to low-lying HOMOs composed mainly of the Ir d-orbital and the 2-phenylpyridine π (ppyπ) orbital. The methylated and aurated complexes can be oxidized by H2O2 or peracid to give sulfinate-thiother, disulfoxide, and sulfinate-sulfoxide complexes, and the oxygenation further stabilizes the HOMO. All the complexes are luminescent, and their electronic spectra are interpreted with the aid of time-dependent density functional theory calculations. The thiother-thiolate complex exhibits ligand(S)-to-ligand(π* of ppy)-charge-transfer/metal-to-ligand-charge-transfer absorption (LLCT/MLCT) and a relatively low-energy (3)LLCT/MLCT emission, while the other complexes display (3)ππ*/MLCT emissions.

A new intersection between reaction chemistry and electronic circuitry is emerging from the ultraminiaturization of electronic devices. Over decades chemists have developed a nuanced understanding of stereoelectronics to establish how the electronic properties of molecules relate to their conformation; the recent advent of single-molecule break-junction techniques provides the means to alter this conformation with a level of control previously unimagined. Here we unite these ideas by demonstrating the first single-molecule switch that operates through a stereoelectronic effect. We demonstrate this behaviour in permethyloligosilanes with methylthiomethyl electrode linkers. The strong σ conjugation in the oligosilane backbone couples the stereoelectronic properties of the sulfur-methylene σ bonds that terminate the molecule. Theoretical calculations support the existence of three distinct dihedral conformations that differ drastically in their electronic character. We can shift between these three species by simply lengthening or compressing the molecular junction, and, in doing so, we can switch conductance digitally between two states.

A series of benzene derivatives with different substituents adsorbed on graphene was investigated using a density-functional tight-binding method with a dispersion correction. Compared to benzene, the derivative with either an electron-withdrawing or -donating substituent exhibits stronger physisorption. Moreover, the steric size of the substituent is important in determining the adsorption strength, while the direction and the number of H atoms in the substituent affect the electron transfer from graphene. NBO analysis reveals that the stereoelectronic effect of the conjugation between the substituent and the benzene ring strongly influences the π···π interaction region between the molecule and graphene. The findings can deepen the understanding of the interaction between an aromatic molecule and graphene as well as the corresponding adsorption mechanism.

The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom – some of them can melt without decomposition at temperatures exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in molecules where two peroxide moieties are separated by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.

Proline is unique among proteinogenic amino acids because a pyrrolidine ring links its amino group to its side chain. This heterocycle constrains the conformations of the main chain and thus templates particular secondary structures. Proline residues undergo post-translational modification at the 4-position to yield 4-hydroxyproline, which is especially prevalent in collagen. Interest in characterizing the effects of this modification led to the use of 4-fluoroprolines to enhance inductive properties relative to the hydroxyl group of 4-hydroxyproline and to eliminate contributions from hydrogen bonding. The strong inductive effect of the fluoro group has three main consequences: enforcing a particular pucker upon the pyrrolidine ring, biasing the conformation of the preceding peptide bond, and accelerating cis/trans prolyl peptide bond isomerization. These subtle, yet reliable modulations make 4-fluoroproline–incorporation a complement to traditional genetic approaches for exploring structure–function relationships in peptides and proteins, as well as for endowing peptides and proteins with conformational stability.

A time-resolved kinetic study of the hydrogen atom transfer (HAT) reactions from a series of alkanamides to the cumyloxyl radical (CumO(•)) was carried out. With N,N-dialkylformamides HAT preferentially occurs from the formyl C-H bond, while in N-formylpyrrolidine HAT mostly occurs from the ring α-C-H bonds. With the acetamides and the alkanamides almost exclusive HAT from the C-H bonds that are α to nitrogen was observed. The results obtained show that alignment between the C-H bond being broken and the amide π-system can lead to significant increases in the HAT rate constant (kH). This finding points toward the important role of stereoelectronic effects on the HAT reactivity and selectivity. The highest kH values were measured for the reactions of CumO(•) with N-acylpyrrolidines. These substrates have ring α-C-H bonds that are held in a conformation that is optimally aligned with the amide π-system, thus allowing for the relatively facile HAT reaction. The lowest kH value was measured for the reaction of N,N-diisobutylacetamide, wherein the steric bulk associated with the N-isobutyl groups increases the energy barrier required to reach the most suitable conformation for HAT. The experimental results are well supported by the computed BDEs for the C-H bonds of the most representative substrates.

Many interests have been focused on prolyl cis-trans isomerization which is related to protein folding and isomer-specific biochemical recognition. Since polyproline can adopt either type I (PPI) helices with all cis amide bonds or type II (PPII) helices with all trans amide bonds, it has been a valuable model to study the prolyl isomerization. Recent studies have shown that stereoelectronic effects govern the stability of PPII structure and the rate of PPII → PPI conversion. To further explore the terminal stereoelectronic effects on polyproline conformation, herein we synthesized a series of host-guest peptides in which (2S,4S)-4-fluoroproline (flp) or (2S,4R)-4-fluoroproline (Flp) residues are incorporated into the C- or N-terminal end of a peptide and studied the thermodynamic and kinetic consequences on polyproline conformation. Circular dichroism measurements revealed that inserting 4-fluoroproline residues into the C terminus of a polyproline peptide induces a great stereoelectronic effect on PPII stability and PPII → PPI conversion rates. From the C terminus, a (Flp)₃ triplet stabilizes PPII structure and increases the transition barrier of PPII → PPI conversion by 1.53 kJ mol⁻¹ while a (flp)₃ triplet destabilizes PPII conformation and reduce the PPII → PPI transition barrier by 4.61 kJ mol⁻¹. In contrast, the 4-fluoroproline substitutions at the N terminus do not exhibit distinct stereoelectronic effects on PPII stability and PPII → PPI conversion rates. Our data demonstrate that the C-terminal stereoelectronic effects have a more dramatic impact on PPII stability and PPII → PPI conversion kinetics.

The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.

The folding of proteins is directed by a variety of interactions, including hydrogen bonding, electrostatics, van der Waals' interactions, and the hydrophobic effect. We have argued previously that an n→π* interaction between carbonyl groups be added to this list. In an n→π* interaction, the lone pair (n) of one carbonyl oxygen overlaps with the π* antibonding orbital of another carbonyl group. The tendency of backbone carbonyl groups in proteins to engage in this interaction has consequences for the structures of folded proteins that we unveil herein. First, we employ density functional theory to demonstrate that the n→π* interaction causes the carbonyl carbon to deviate from planarity. Then, we detect this signature of the n→π* interaction in high-resolution structures of proteins. Finally, we demonstrate through natural population analysis that the n→π* interaction causes polarization of the electron density in carbonyl groups and detect that polarization in the electron density map of cholesterol oxidase, further validating the existence of n→π* interactions. We conclude that the n→π* interaction is operative in folded proteins.

The positive hyperfine coupling constants of the geminal 1H nuclei in cis-1,2-dimethyl- and cis-1,2-diphenylcyclopropane radical cations show a significant stereoelectronic effect: the 1H nuclei trans (anti) to the substituents are coupled much more strongly than the corresponding nuclei cis (syn) to them. Theoretical calculations on these radical cations and on bismethano[2,2]paracylophane as well as new 1H-CIDNP experiments at 200 Mz elucidate the general features of these systems. Copyright © 2014 John Wiley & Sons, Ltd.

The combination of experiments and computations reveals unusual features of stereoselective Rh(I)-catalyzed transformation of propargyl vinyl ethers into (E,Z)-dienals. The first step, the conversion of propargyl vinyl ethers into allene aldehydes, proceeds under homogeneous conditions via a "cyclization-mediated" mechanism initiated by Rh(I) coordination at the alkyne. This path agrees well with the small experimental effects of substituents on the carbinol carbon. The key feature revealed by the computational study is the stereoelectronic effect of the ligand arrangement at the catalytic center. The rearrangement barriers significantly decrease due to the greater transfer of electron density from the catalytic metal center to the CO ligand oriented trans to the alkyne. This effect increases electrophilicity of the metal and lowers the calculated barriers by 9.0 kcal/mol. Subsequent evolution of the catalyst leads to the in situ formation of Rh(I) nanoclusters that catalyze stereoselective tautomerization. The intermediacy of heterogeneous catalysis by nanoclusters was confirmed by mercury poisoning, temperature-dependent sigmoidal kinetic curves, and dynamic light scattering. The combination of experiments and computations suggests that the initially formed allene-aldehyde product assists in the transformation of a homogeneous catalyst (or "a cocktail of catalysts") into nanoclusters, which in turn catalyze and control the stereochemistry of subsequent transformations.

In this study, we reported a potential method of constructing six-membered nitrogen-containing heterocycles via intramolecular cyclization of R 2 -substituted 4-penteniminyl radicals (R 2 = –NO 2 , –SO 2 OH, –CF 3 , –SO 2 Ph, –CN, –CONMe 2 , – p -PhNO 2 , and –COOH). All of these investigated iminyl radicals exhibit strong preference for 6- endo cyclization products over 5- exo products. We further explored possible reasons to lead to the predominant 6- endo regioselectivity, including electronic density, stereoelectronic effect (intrinsic barrier), and thermodynamic contribution to reaction barrier. The computed results provided a potential synthetic strategy towards constructing six-membered N-heterocycles by intramolecular cyclization of substituted iminyl radicals.

Switching of the magnetic exchange coupling from ferro- to antiferromagnetic or vice versa in a single molecule is an appealing but rarely occurring phenomenon in molecular magnetism. Here, we report this for an unprecedented pure organic system, computationally designed by tailoring a conformationally restricted, known nitroxide-diradical (Rajca et al. J. Am. Chem. Soc. 2007, 129, 10159). This ferro- to antiferromagnetic coupling switching of an "m-phenylene" based diradical is governed by a stereoelectronic effect and controlled by a redox-driven chemical reaction.

Density functional theory (B3LYP/cc-pVDZ//B3LYP/cc-pVDZ) is used to optimize the geometries of 1,2,7-thiadiazepane and natural bond orbital (NBO) analyses have been carried out employing the HF/6-31G(d,p) level using B3LYP/cc-pVDZ geometries to study the stereoelectronic effects on the stability of the stereoisomers (axial–axial, equatorial–equatorial, and axial–equatorial). The results of NBO calculations showed that the axial–axial or axial–equatorial stereoisomers are the most stable conformers, where not only the stereoelectronic effect, but also the steric repulsion significantly affects their stability.

A mechanism about the origin of the selectivities for the cleavage of dioxolane five-membered rings on pyranoside rings was suggested. Quantum chemical studies were performed to testify the rationality of the mechanism. It is thus suggested that the selectivities should be dependent on the differences of the free energy at the transition states when the five-membered ring cleaves. Natural bond orbital(NBO) analysis was further made to assess the influence of stereoelectronic effects on the selectivities.

Hydroacylation reactions and aza-benzoin reactions have attracted considerable attention from experimental chemists. Recently, Wang et al. reported an interesting reaction of N-heterocyclic carbene (NHC)-catalyzed addition of aldehyde to enamide, in which both hydroacylation and aza-benzoin reactions may be involved. Thus, understanding the competing relationship between them is of great interest. Now, density functional theory (DFT) investigation was performed to elucidate this issue. Our results reveal that enamide can tautomerize to its imine isomer with the assistance of HCO3−. The addition of NHC to aldehydes formed Breslow intermediate, which can go through cross-coupling with enamide via hydroacylation reaction or its imine isomer via aza-benzoin reaction. The aza-benzoin reaction requires relatively lower free energy barrier than the hydroacylation reaction. The more polar characteristic of C=N group in the imine isomers, and the more advantageous stereoelectronic effect in the carbon-carbon bond forming transition states in aza-benzoin pathway were identified to determine that the imine isomer can react with the Breslow intermediate more easily. Furthermore, the origin of enantioselectivities for the reaction was explored and reasonably explained by structural analyses on key transition states. The work should provide valuable insights for rational design of switchable NHC-catalyzed hydroacylation and aza-benzoin reactions with high stereoselectivity.

The cerium-catalyzed, aerobic coupling of β-oxoesters with enol acetates and dioxygen yields δ-lactones with a 1,4-diketone moiety. In contrast to the Baeyer-Villiger oxidation (BVO), where the higher substituted residue migrates; in the case of this oxidative C-C coupling reaction, the less substituted alkyl residue undergoes a 1,2-shift. An endoperoxidic oxycarbenium ion comparable to the Criegee intermediate in the BVO is proposed as a reaction intermediate and submitted to conformational analysis by computational methods. As a result, the inverse regiochemistry is explained by a primary stereoelectronic effect. A Hammett analysis using different donor- and acceptor-substituted enol esters provides support for the oxycarbenium ion being the crucial intermediate in the rate determining step of the conversion. An overall mechanism is suggested with a radical chain reaction for the formation of endoperoxides from β-oxoesters, enol acetates and dioxygen with a cerium(IV) species as initiating reagent.

An efficient two-step synthesis of structure- and function-diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. Our syntheses of MAHTs and MAHOs, the majority of which have not been previously reported, is readily scalable affording gram quantities of product. In a hydrogen deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen deuterium exchange and levels of isotope incorporation were observed. By way of example, using [2H]methanol and 4-bromophenol-derived MAHO afforded only 14% [2H]-incorporation (9 minutes, k = 31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97% [2H]-incorporation (9 minutes, k = 208). In a benchmarked procedure and comprehensive DFT study 54 ester and thioester configurations and conformations where characterised. This established in the MAHT series a sulfur-containing molecular orbital provides a path for increased delocalisation of electron-density into the enol which is unavailable in MAHOs, which facilitates keto-enol tautomerisation and consequently enhances the rate and percentage of hydrogen deuterium exchange.

The synthesis of a series of conformationally locked mannopyranosyl thioglycosides in which the C6-O6 bond adopts either the gauche,gauche, gauche,trans, or trans,gauche conformation is described, and their influence on glycosylation stereoselectivity investigated. Two 4,6-O-benzylidene-protected mannosyl thioglycosides carrying axial or equatorial methyl groups at the 6-position were also synthesized and the selectivity of their glycosylation reactions studied to enable a distinction to be made between steric and stereoelectronic effects. The presence of an axial methoxy group at C6 in the bicyclic donor results in a decreased preference for formation of the β-mannoside, whereas an axial methyl group has little effect on selectivity. The result is rationalized in terms of through-space stabilization of a transient intermediate oxocarbenium ion by the axial methoxy group resulting in a higher degree of SN 1-like character in the glycosylation reaction. Comparisons are made with literature examples and exceptions are discussed in terms of pervading steric effects layered on top of the basic stereoelectronic effect.