Transannular Interaction Research Articles

Ruthenium-Catalyzed Carbonylation of α-Aminoaryl-Tethered Alkylidenecyclopropanes: Synthesis of Eight-Membered Benzolactams.

The synthesis of medium-sized lactams is a great challenge because of the unfavorable transannular interactions and entropic barriers in the transition state. We have developed a ruthenium-catalyzed carbonylation of α-aminoaryl-tethered alkylidenecyclopropanes (ACPs) that allows for the efficient preparation of valuable eight-membered benzolactams under ligand-free conditions. The amino group served a dual role of both directing group and nucleophile to facilitate the metallacycle formation and the carbonylation.

Strained thiacyclophanes: Reducing properties and gauge of transannular interactions

The current study involves the investigation of reducing properties of disulfide bonded heteraphanes. The calculated adiabatic electron affinity (AEA) values of heteraphanes are found comparable to that of cystine molecule and are capable of undergoing reversible redox reactions. In aqueous phase, these show high propensity to get reduced. The reaction energies calculated using isodesmic equations reflect the strain associated with the studied thiacyclophane models. Increase in the number of disulfide bonds results in less strain and more stabilization. Through-space transannular interactions in the selected heteraphanes have a decisive influence on the structure stabilization associated with the systems. The results reported in the current study are expected to play a vital role while designing redox driven drug carriers by incorporating these systems in biomolecules.

Ten-Membered Cyclodecatetraene Derivatives Including Two Gallium Atoms: Experimental and Theoretical Studies on Synthesis, Structures, and Their Transformations to Nine- and Five-Membered Gallacycles

The chemistry of medium-sized ring compounds, including group 13 elements, has scarcely been investigated. Herein, we report that 5,10-digallacyclodeca-1,3,6,8-tetraene derivatives Cl2Ga2C8R8 (R = Me (5a), Et (5b)) can be obtained by the reaction of GaCl3 and zirconacyclopentadiene Cp2ZrC4R4 (R = Me (2a), Et (2b), Cp: η5-C5H5) in toluene. X-ray crystal structure analysis revealed that compound 5b has a 10-membered cyclodecatetraene structure composed of two butadiene skeletons and two GaCl fragments. X-ray crystal structure analysis and IR measurement confirmed that compound 5b forms Ga2Cl2 four-membered rings via intermolecular Cl to Ga donor–acceptor interactions, which result in the formation of oligomeric chain structures in the solid state and toluene solution. The treatment of compound 5b with 2 equivalents of 4-(dimethylamino)pyridine (DMAP) proceeded via the coordination of DMAP to the Ga center and the ring contraction to give DMAP-coordinated five-membered gallole Cl(DMAP)GaC4Et4 (4bDMAP). The reaction of compound 5a with 2 equivalents of MesLi (Mes: 2,4,6-Me3C6H2) in toluene to form a 9,10-digallabicyclo[4.3.1]decatriene derivative (MesGaC8Me8)GaMes (6a) caused ring contraction. Theoretical investigation revealed that the 10-membered ring derivative, Cl2Ga2C8H8 (GaH-10), is formed by the dimerization of two gallole molecules, ClGaC4H4 (GaH-5), via the addition of two Ga–C bonds without an energy barrier. The immediate formation of GaH-10 was attributed to the transannular electronic interaction between the expanded empty p-orbital on the Ga atom and the electron-rich sp2 carbons of the C═C double bond in GaH-5. Moreover, GaH-10 and one of the isomer, nine-membered ring derivative (ClGaC8H8)GaCl, were found to be thermodynamically more stable, as compared to GaH-5.

Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design.

As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range of related hypothetical systems have been investigated, together with transannular interactions involving ring-embedded imino or azo group nitrogens and atoms or groups (Y) across the ring. Electrostatic potential energies mapped onto electron density surfaces in the different ring conformations were evaluated in order to characterise these conformations. Unexpectedly, the presence of sp2 hybridised nitrogen atoms in the medium-sized rings did not influence the conformations appreciably. The strength and type of the N…Y interactions are determined primarily by the nature of Y. This is also the case when the substituent on the interacting nitrogen is varied from CH3 (protopine) to H or OH. With Y = BOH, very strong interactions were observed in protopine analogues, as well as in rings incorporating imino or azo groups. Strong to moderate interactions were observed with Y = CS, CO and SO in all ring systems. Weaker interactions were observed with Y = S, O and weaker ones again with an sp3 hybridised carbon (Y = CH2). The transannular interactions can influence conformational preferencing and shape and change electron distributions at key sites, which theoretically could modify properties of the molecules while providing new or enhanced sites for biological target interactions, such as the H or OH substituent. The prediction of new strong transannular interaction types such as with Y = BOH and CS should be helpful in informing priorities for synthesis and other experimental studies.

Tuning of Cu–Al Interactions in Complexes Derived from Tris(pyridonyl-6-methyl)aluminum Metalloligands

A series of bioinspired polar atrane Cu-Al complexes were studied with a combined experimental and computational approach to assess the range and nature of Cu-Al interactions in these novel species. The aluminum metalloligand [Na{Me2Al(OPy-6-Me)2}] (2) was furnished in excellent yield (92%) from the nucleophilic attack of Na(OPy-6-Me) to AlMe3 and the subsequent alkane elimination reaction with 6-methyl-2-hydroxypyridine. At the same time, the metalloligand [Al(OPy-6-Me)3] (3) was isolated in an also excellent yield (95%) via alkane elimination of AlMe3 with 6-methyl-2-hydroxypyridine. The zwitterionic Cu-Al atranes [Cu{MeAl(OPy-6-Me)3}] (5Me) and [Cu{MesAl(OPy-6-Me)3}] (5Mes) were isolated (73 and 97% yields) from metalloligands 2 and 3, respectively. [(Cu{Al(OPy-6-Me)4})2(μ-Cu)]+ ([6+][B(ArCF3)4]) was isolated via a reaction that involves alkane elimination and redistribution reacting from 5Me with [H(OEt2)2][B(ArCF3)4] in benzene solution. Alkane elimination in benzene of either 5Me or 5Mes with [HNEt3][B(ArCF3)4] renders [Cu{(Et3N)Al(OPy-6-Me)3}]+ (Et3N-5+). The Lewis base-free cationic complex [Cu{Al(OPy-6-Me)3}]+ (5+) was isolated in 68% yield upon reacting 3 with [Cu(COD)2][B(ArCF3)4] in benzene. Metalloligands and complexes were fully characterized with an array of spectroscopic and analytical techniques that include multinuclear NMR, ATR-IR, ESI-spectrometry, combustion microanalysis, cyclic voltammetry (CV), and, whenever feasible, SCXRD. X-ray and DFT parameters indicate that the strength of the Cu→Al transannular interaction follows the trend 5+ > Et3N-5+ > [6+][B(ArCF3)4], 5Me, and 5Mes in a smooth transition from zwitterionic species where the Cu-Al interaction is nonexistent to moderate Cu-Al Z-type interactions. CV, in conjunction with DFT calculations of Et3N-5+ and 5+, hint at the generation in the electrochemical cell of the radical species 5rad at -1.82 V and the anionic complex 5- at -2.32 V vs Fc/Fc+, respectively. The proposed species 5rad exhibits 2-center/1-electron (2c/1e) σ bonding whereas 5- a 2-center/2-electron (2c/2e) bond.

Recent advances in transition-metal-catalyzed Büchner reaction of alkynes.

Medium-sized ring-containing organic molecules, especially seven-membered rings, are significant structural motifs. However, such frameworks are considered difficult structures to access owing to entropic effects and transannular interactions. Compared to the construction of five and six-membered rings, the synthesis of seven-membered rings can be more challenging through traditional cyclization pathways. Büchner reactions are particularly attractive and efficient synthetic strategies to construct functionalized seven-membered ring products from the benzenoid double bond with carbene. In recent years, the field of transition-metal-catalyzed Büchner ring expansion reactions of alkynes has experienced a speedy development and a diverse array of efficient synthetic procedures have been disclosed under mild experimental conditions, as the synthesis of synthetically challenging seven-membered rings is easily achieved. In this review, we will focus on the recent progress in the transition-metal-catalyzed Büchner reaction of alkynes and the mechanistic rationale is depicted where possible, with the reactions being sorted according to the type of catalyst.

Simulation Reveals the Chameleonic Behavior of Macrocycles.

Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations─standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.

Rhodium-Catalyzed Asymmetric (3 + 2 + 2) Annulation via N–H/C–H Dual Activation and Internal Alkyne Insertion toward N-Fused 5/7 Bicycles

N-Fused 5/7-membered bicycles have witnessed apparent importance in many bioactive molecules, but there are rare examples to construct these privileged scaffolds by asymmetric catalysis due to the unfavorable steric hindrance, transannular interactions, and congested bridgehead stereocenter. We herein report rhodium-catalyzed (3 + 2 + 2) annulation of alkenylamides with alkynes for the efficient synthesis of stereogenic 1-azabicyclo[5.3.0]decanes through N–H/C–H bond dual activation. Moreover, the corresponding asymmetric catalytic reaction has been realized leading to enantioenriched products bearing bridgehead quaternary stereocenter in moderate-to-good yields with up to 96% ee. Mechanistic studies and density functional theory calculations have revealed that rhodium experienced a preset unique catalytic pathway via amino rhodation of tethered ene to produce a stereogenic alkyl-Rh species, which undergoes the following C–H activation and alkyne insertion to provide the key 8-membered rhodacycle intermediate. This protocol discloses a highly valuable asymmetric rhodium-mediated C–H functionalization mode and validates a de novo cascade construction of chiral 1-azabicyclo[5.3.0]decanes.

Metallacyclosilanes of Calcium, Yttrium, and Iron.

Utilizing a choice of α,ω-oligosilanylene diides, it is possible to synthesize a number of heterocyclosilanes with heteroelements of calcium, yttrium, and iron by metathesis reactions with respective metal halides CaI2, YCl3, and FeBr2. 29Si NMR spectroscopic analysis of the calcacyclosilanes suggests that these compounds retain a strong oligosilanylene dianion character, which is more pronounced than in the analogous magnesacyclosilanes. As the electronegativity of calcium lies between potassium and magnesium, silyl calcium reagents should be considered as building blocks with an attractive reactivity profile. Reaction of a 1,4-oligosilanylene diide with YCl3 gave the five-membered yttracyclosilane as an ate-complex with two chlorides still attached to the yttrium atom. Reaction of the obtained compound with two equivalents of NaCp led to another five-membered yttracyclosilane ate-complex with an yttracene fragment. When using a dianionic oligosilanylene ligand containing a siloxane unit, the siloxane oxygen acted as an additional coordination site for Ca and Y. When the same ligand was used to prepare a cyclic 1-ferra-4-oxatetrasilacyclohexane, an analogous transannular interaction between the iron and oxygen atoms is missing.

Spectroscopic, quantum chemical and molecular docking studies on friedelin, the major triterpenoid isolated from Garcinia imberti

Friedelin, a Garcinia imberti isolate, was subjected to a detailed theoretical study using the density functional theory. Theoretical calculations, such as optimized geometry, electronic, vibrational spectroscopic, intermolecular interactions, and insilico screening were performed. DFT at hybrid functional B3LYP was chosen, and the 6–311++G(d, p) level of theory was used for all simulations. The first three rings of the compound are in chair conformation (trans arrangement), while the remaining two rings are in boat conformation (cis arrangement). Transannular, flagpole, and stereo electronic hyperconjugative interactions are observable throughout the optimal geometry because of the conformation therein. Non-covalent H...H interactions is also confirmed by Hrishfeld surface analysis. NBO and NPA analyses have confirmed stereo electronic hyperconjugative interactions and C-H...O intramolecular hydrogen bonding interactions. The estimated vibrational wavenumbers and the experimentally determined values have an excellent correlation. The TD-DFT computations were performed both in solvent (chloroform) and gaseous phase, and agree with the experimental values. The molecule was tested insilico against tuberculosis protein 4FDO using the Schrodinger suite's Glide docking software. After the docking studies, the compound's drug-likeness and ADMET predictions were calculated, and the results indicated that it could be exploited as a tuberculosis treatment option.

Density functional theory assessment of transannular N⋯Y interactions in some medium-sized heterocycles

Transannular interactions involving a nitrogen and groups Y in ten-membered rings based on the alkaloid protopine were studied by DFT methodology to investigate the potential mimicking of shapes and electrostatic potentials and thus biological activities of fused berberine and related analogues. The methodology was confirmed for protopine (YCO) and the transannular N⋯CO interaction rationalised as an n → π* interaction. With YCS, the same interaction was observed, as well as structures with NC single bonds. With YBOH, structures with dative NB single bonds were found. In all three cases, the structures with transannular interactions were more energetically favourable than “wide” conformations. To quantify the interactions, topological density-based descriptors, natural bond orbital charges and overlap energies and electrostatic potential-derived (ESP) charges were calculated. Visualisation of electron densities and ESPs mapped onto the densities was explored. The scope of the transannular N⋯Y interaction was examined with an additional five Y groups.

Seven Conformations of the Macrocycle Cyclododecanone Unveiled by Microwave Spectroscopy

The physicochemical properties and reactivity of macrocycles are critically shaped by their conformations. In this work, we have identified seven conformations of the macrocyclic ketone cyclododecanone using chirped-pulse Fourier transform microwave spectroscopy in combination with ab initio and density functional theory calculations. Cyclododecanone is strongly biased towards adopting a square configuration of the heavy atom framework featuring three C–C bonds per side. The substitution and effective structures of this conformation have been determined through the observation of its 13C isotopologues. The minimisation of transannular interactions and, to a lesser extent, HCCH eclipsed configurations drive conformational preferences. Our results contribute to a better understanding of the intrinsic forces mediating structural choices in macrocycles.

Regio and stereochemical probes of iodine interactions in diiodocyclododecanes

AbstractCyclododecane preferentially adopts a square‐like geometry, giving rise to corner and edge methylene (CH2) groups, whose hydrogens assume different orientations. In edge CH2 groups, hydrogens can be inward‐ (endo) and outward‐looking (exo) the ring. Herein, we have quantum‐chemically studied the replacement of two hydrogens in cyclododecane with iodines at the relative positions 1,4, 1,5, 1,6, and 1,7. Intramolecular interactions are only slightly unfavorable in 1,7‐diiodocyclododecane containing the organic iodines in the edge/endo positions, less than expected from steric considerations. This behavior was discussed in terms of transannular interactions, and a numerical estimation for the magnitude of the intramolecular interaction energy has been performed based on an isodesmic reaction scheme and by natural energy decomposition analysis. 1,5‐Diiodocyclododecane with both edge iodines in the endo orientation (occupying opposite faces of the ring) is strongly favored (by ca. 2.0 kcal mol−1) compared to the respective monosubstituted counterparts, due to highly stabilizing hyperconjugative interactions. Although halogen bonding involving anionic species is widely known, we show that organic halogens, in particular iodine, can be useful for stereochemical control in macrocycles.

Small Figure-Eight Luminophores: Double-Twisted Tethered Cyclic Binaphthyls Boost Circularly Polarized Luminescence.

Invited for the cover of this issue are Masashi Hasegawa, Yoshitane Imai and co-workers at Kitasato University and Kindai University. The image depicts the reported figure-eight molecule as an M. C. Escher-inspired 'impossible object'. Read the full text of the article at 10.1002/chem.202005320.

Small Figure-Eight Luminophores: Double-Twisted Tethered Cyclic Binaphthyls Boost Circularly Polarized Luminescence.

Double-twisted cyclic binaphthyls, in which two naphthalenes are tethered by -O(CH2 )n O- linkage (n=1-3), have been synthesized. X-ray analyses and DFT calculations revealed a tightly constrained stereogenic figure-eight geometry. Tethering of two naphthalenes by short linkage forces a small dihedral angle, and the cyclic binaphthyls with short tether (n=1, 2) exhibit remarkable boosting of the glum value (1.0-1.6×10-2 ) in circularly polarized luminescence (CPL) and unusual glum /gabs ratios (0.93-1.3). These experimental high |glum | values are in accord with the results of excited state TD-DFT calculations, which show transannular interactions and that consequent extensive delocalization occurs throughout the figure-eight π-core. As a result, the present figure-eight luminophore promote the elongation of the magnetic transition dipole moment that results in significant increases in glum values.

Mechanism of the Asymmetric Dehydrative Allylative Cyclization of Alcohols to Cyclic Ethers Catalyzed by a CpRu Complex of the Chiral Picolinic Acid-Type Ligand, Cl-Naph-PyCOOH: Is a π-Allyl Intermediate Present?

Abstract [Ru(II)Cp((R)-Cl-Naph-PyCOOH)]PF6 ((R)-1) catalyzes the dehydrative cyclization of (E)-hept-2-ene-1,7-diol (2) to 2-vinyltetrahydro-2H-pyran (3) with a 97:3 S/R enantiomer ratio. Complex (R)-1 is in equilibrium between two diastereomers (R,RRu)-1 (AR) and (R,SRu)-1 (AS). A difference of turn over efficiency between the AS and AR cycles is thought to be the origin of the high enantioselectivity. The AS gives a major enantiomeric product (S)-3, according to the results of detailed mechanistic investigation via i) X-ray crystallographic analysis of related complexes, ii) NMR experiments using allylic alcohol 2, OH-lacking 2-mimic 4, d-labeled (S)-4-1d, enantiomerically enriched hept-6-ene-1,5-diol (6) as branched isomer of 2, and OH-lacking 6-mimic 5, iii) substrate structure/reactivity and selectivity relationships, iv) deuterium-labeling experiment, v) kinetics via calorimetric analysis, and vi) ligand structure/reactivity and selectivity relationships. AS captures 2 via hydrogen and halogen bonds. Oxidative addition in an H2Oin mode leads to a macrocyclic σ-allyl intermediate. Here, an efficient nC(7)OH/π*C(3)=C(2) trans-annular (TA) interaction facilitates an SN2′ nucleophilic addition of OH in an OHTA manner to furnish (S)-3. Contrary to the AS, AR cannot capture 2 using the halogen bond and slowly operates to give (R)-3. A conventional π-allyl-complex-involved mechanism is ruled out by a contradiction in the result of ii) and iii).

Synthesis of Medium-Sized Heterocycles by Transition-Metal-Catalyzed Intramolecular Cyclization.

Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In particular, methods involving intramolecular bond formation are challenging due to unfavorable enthalpic and entropic factors, such as transannular interactions and conformational constraints. The present review focuses on the synthesis of medium-sized heterocycles by transition-metal-catalyzed intramolecular cyclization, which despite its drawbacks remains a straightforward and attractive synthesis strategy. The obtained heterocycles differ in their nature, number of heteroatoms, and ring size. The methods are classified according to the metal used (palladium, copper, gold, silver), then subdivided according to the type of bond formed, namely carbon–carbon or carbon–heteroatom.

Easy access to medium-sized lactones through metal carbene migratory insertion enabled 1,4-palladium shift

Reactions that efficiently construct medium-sized lactones are significant, as they overcome the unfavorable entropic factor and transannular interactions for ring closure, and the lactones produced are common structural motifs recurring in many biologically active compounds. Herein, we describe a valuable strategy for medium-sized lactone synthesis by accomplishing site-selective C–H bond functionalization via a palladium carbene migratory insertion enabled 1,4-palladium shift. The overall process achieves the formal dimerization of two readily available benzaldehyde derivatives, providing value-added products medium-sized lactones. Our method is amenable to late-stage modification of approved drugs and other complex molecules. Mechanistic studies including deuterium-labeling experiments and DFT calculation shed light on the reaction pathways.

Conformational Control of Macrocycles by Remote Structural Modification.

The conformational analysis of macrocycles is a complex and challenging problem. There are many factors that contribute to this complexity. These include a large number of degrees of freedom, transannular interactions such as hydrogen bonds and hydrophobic interactions, and a range of steric interactions, along with ring strain effects. To a greater extent than within acyclic molecules, these interactions within macrocycles are coupled such that changing one dihedral angle can significantly affect other dihedral angles, further complicating the situation. However, this coupling of bond rotations and transannular interactions enables the transmission of three-dimensional information from one side of a macrocycle to the other. Making relatively small structural modifications to a macrocycle can result in local conformational changes that propagate along the ring to affect distal structural features. The factors that control how such changes can propagate are poorly understood, and it is difficult to predict which modifications will result in significant conformational reorganizations of remote regions of a macrocycle. This review discusses examples where small structural modifications to macrocyclic scaffolds change the conformational preferences of structurally remote regions of the ring. We will highlight evidence provided for conformational changes triggered by remote substituents and explanations of how these changes might occur in an effort to further understand the factors that control such phenomena.

Indeno[1,2‐b]fluorene‐Based [2,2]Cyclophanes with 4n/4n and 4n/[4n+2] π Electrons: Syntheses, Structural Analyses, and Excitonic Coupling Properties

AbstractIndeno[1,2‐b]fluorene‐based [2,2]cyclophanes with 4n/4n and 4n/[4n+2] π‐electron systems were prepared, and their structures were identified by X‐ray crystallography. With short π–π distances around 3.0 Å, [2.2](5,11)indeno[1,2‐b]fluorenophane and its precursor [2.2](5,11)indeno[1,2‐b]fluorene‐6,12‐dionophane exhibit remarkable transannular interactions, leading to their unusual electrochemical and photophysical properties. With the aid of femtosecond transient absorption spectroscopy, the transition from the monomeric excited state to the redshifted H‐type dimeric state was first observed, correlating to the calculated excitonic energy splitting and the steady‐state absorption spectra induced by charge‐transfer‐mediated superexchange interaction.