Simple Access to Highly Functional Bicyclic γ‐ and δ‐Lactams: Origins of Chirality Transfer to Contiguous Tertiary/Quaternary Stereocenters Assessed by DFT

This paper describes the synthesis of both polysubstituted oxazolo‐pyrrolidinones and ‐piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron‐withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)‐phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereoselectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.     

Redox‐Triggered Reversible Interconversion of a Monocyclic and a Bicyclic Phosphorus Heterocycle

Molecules which change their structures significantly and reversibly upon an oxidation or reduction process have potential as future components of smart materials. A prerequisite for such an application is that the molecules should undergo the redox‐coupled transformation within a reasonable electrochemical window and lock into stable redox states. Sodium phosphaethynolate reacts with two equivalents of dicyclohexylcarbodiimide (DCC) to yield an anionic, imino‐functionalized 1,3,5‐diazaphosphinane [ 3 a ]^?. The oxidation of this anion with elemental iodine causes an intramolecular rearrangement reaction to give a bicyclic 1,3,2‐diazaphospholenium cation [ 6 ]⁺. This umpolung of electronic properties from non‐aromatic to highly aromatic is reversible, and the cation [ 6 ] ⁺ is reduced with elemental magnesium to reform the 1,3,5‐diazaphosphinanide anion [ 3 a ]^?. Theoretical calculations suggest that phosphinidene species are involved in the rearrangement processes.     

Identification of a Lead Candidate in the Search for Carbene‐Stabilised Homoaromatics

The effect of carbenes as Lewis donor groups on the homoaromaticity of mono‐ and bicyclic organic molecules is surveyed. The search for viable carbene‐stabilised homoaromatics resulted in a large amount of rejected candidates as well as nine promising candidates that are further analysed for their homoaromaticity by using a number of metrics. Of these, five appeared to show modest homoaromaticity, whereas another compound showed a level of homoaromaticity comparable with the homotropylium cation benchmark compound. Isoelectronic analogues and constitutional isomers of the lead compound were investigated, however, none of these showed comparable homoaromaticity. The implications of these calculations on the design of donor‐stabilised homoaromatics are discussed.     

Bromenium‐Catalysed Tandem Ring Opening/Cyclisation of Vinylcyclopropanes and Vinylcyclobutanes: A Metal‐Free [3+2+1]/[4+2+1] Cascade for the Synthesis of Chiral Amidines and Computational Investigation

We present a detailed study of a [3+2+1] cascade cyclisation of vinylcyclopropanes (VCP) catalysed by a bromenium species (Br^δ+? X^δ?) generated in situ, which results in the synthesis of chiral bicyclic amidines in a tandem one‐pot operation. The formation of amidines involves the ring‐opening of VCPs with Br? X, followed by a Ritter‐type reaction with chloramine‐T and a tandem cyclisation. The reaction has been further extended to vinylcyclobutane systems and involves a [4+2+1] cascade cyclisation with the same reagents. The versatility of the methodology has been demonstrated by careful choice of VCPs and VCBs to yield bicyclo[4.3.0]‐, ‐[4.3.1]‐ and ‐[4.4.0]amidines in enantiomerically pure form. On the basis of the experimental observations and DFT calculations, a reasonable mechanism has been put forth to account for the formation of the products and the observed stereoselectivity. We propose the existence of a π‐stabilised homoallylic carbocation at the cyclopropane carbon as the reason for high stereoselectivity. DFT studies at B3LYP/6‐311+G** and M06‐2X/6‐31+G* levels of theory in gas‐phase calculations suggest the ring‐opening of VCP is initiated at the π‐complex stage (between the double bond and Br? X). This can be clearly perceived from the solution‐phase (acetonitrile) calculations using the polarisable continuum model (PCM) solvation model, from which the extent of the ring opening of VCP was found to be noticeably high. Studies also show that the formation of zero‐bridge bicyclic amidines is favoured over other bridged bicyclic amidines. The energetics of competing reaction pathways is compared to explain the product selectivity.     

A quantum mechanical study of the abstraction reactions of fused bicyclic dimetallenes

The potential energy surfaces for the abstraction reactions of fused bicyclic dimetallene species with carbon tetrachloride have been characterized in detail by using density functional theory including zero-point corrections. All the stationary points were determined at the B3LYP/LANL2DZdp level of theory. Five fused bicyclic dimetallene species including fused bicyclic diethylene, fused bicyclic disilene, fused bicyclic digermene, fused bicyclic distannene, and fused bicyclic diplumbene have been chosen in this work as model reactants. Comparisons of the activation barriers and reaction enthalpies were used to determine the relative reactivity of the fused bicyclic dimetallenes on the reaction potential energy surface. As a result, our theoretical investigations suggest that, irrespectively of the fused bicyclic dimetallene, the Cl-abstraction pathway is more favorable than the CCl3-abstraction pathway from both kinetic and thermodynamic considerations. Moreover, our model calculations indicate that the heavier the group 14 element in the fused bicyclic dimetallenic species, the lower the activation barrier and the more exothermic the haloalkane abstraction. Furthermore, a configuration mixing model based on the work of Pross and Shaik is used to rationalize the computational results. The results obtained allow a number of predictions to be made.     

Alkali Cation Complexation and Transport Properties of Synthetic Bicyclic Decapeptides: Structural,Thermodynamic, and Kinetic Analysis

Alkali cation complexation and bilayer transport by the bicyclic decapeptides S,S′-bis-cyclo-glycyl-L -hemicystyl-glycyl-glycyl-L -prolyl ( 1 ), S, S′-bis-cyclo-glycyl-L -hemicystyl-glycyl-glycyl-D -prolyl ( 2 ), S, S′-bis-cyclo-glycyl-L - hemicystyl-sarcosyl-sarcosyl-L -prolyl ( 3 ), and S, S′-bis-cyclo-glycyl-L -hemicystyl-sarcosyl-sarcosyl-D -prolyl ( 4 ) were analyzed according to structural, thermodynamic and kinetic criteria; valinomycin was used as a reference ionophoretic system. Structural analysis of peptide 3 with spectroscopic methods showed different conformational arrangements in the bicyclic system depending on its state of complexation. Circular dichroism indicated the presence of a multitude of conformations with differing helicities around the disulfide bridge in both free and complexed states. Thermodynamic analysis by microcalorimetry demonstrated a far lower cation selectivity among the synthetic peptides than displayed by valinomycin. Peptide 3 shows cation affinities of about two orders of magnitude higher than peptide 4 , but still much lower than found for the complexes of valinomycin with K⁺ and Rb⁺. In contrast to the latter case, the complexation reactions of peptides 3 and 4 are driven by both enthalpy and entropy contributions. Neither peptide 1 and 2 nor the cyclic partial structures of all four peptides displayed significant cation complexation. A kinetic analysis of the K⁺-complexation by peptide 3 based on the microcalorimetry experiments showed far lower rates of cation exchange for the synthetic peptide than those reported for valinomycin. Transport studies with peptide 3 using artificial lipid bilayer membranes gave negative results. The apparent lack of ionophoretic properties of these synthetic peptides despite their considerable ability to form complexes with cations is discussed in terms of structural parameters.     

Interactions between cyclic carbon clusters

This work reports on the results of MINDO/3 calculations of the structures and energies of monocyclic and bicyclic carbon clusters. Interactions between the rings and between the cyclic and linear clusters are considered. For the most typical reactions (cyclization of linear clusters and insertion of chains into rings and formation of bicyclic structures), the energy barriers are estimated. The bond energies of the bicyclic structures depend on the parities of the initial rings. The most stable configurations with bond energies of the order of 5 eV result from coupling of the odd-membered rings. It is shown that typical condensation conditions correspond to the absorption of the linear clusters by the cyclic structures. Institute of Theoretical and Applied Mechanics, Siberian Branch, Russian Academy of Sciences. Institute of Computational Technologies, Siberian Branch, Russian Academy of Sciences. Translated fromZhurnal Strukturnoi Khimii, Vol. 36, No. 6, pp. 991–997, November–December, 1995. Translated from I. Izvekova     

Cations and Anions of Dibenzo[a,e]pentalene and Reduction of a Dibenzo[a,e]pentalenophane

Dibenzo[a,e]pentalene (DBP) is a non-alternant conjugated hydrocarbon with antiaromatic character and ambipolar electrochemical behavior. Upon both reduction and oxidation, it becomes aromatic. We herein study the chemical oxidation and reduction of a planar DBP derivative and a bent DBP-phane. The molecular structures of its planar dication, cation radical and anion radical in the solid state demonstrate the gained aromaticity through bond length equalization, which is supported by nucleus independent chemical shift-calculations. EPR spectra on the cation radical confirm the spin delocalization over the DBP framework. A similar delocalization was not possible in the reduced bent DBP-phane, which stabilized itself by proton abstraction from a solvent molecule upon reduction. This is the first report on structures of a DBP cation radical and dication in the solid state and of a reduced bent DBP derivative. Our study provides valuable insight into the charged species of DBP for its application as semiconductor.     

Nucleophile‐Dependent Regio‐ and Stereoselective Ring Opening of 1‐Azoniabicyclo[3.1.0]hexane Tosylate

1‐[(1R)‐(1‐Phenylethyl)]‐1‐azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2‐(3‐hydroxypropyl)aziridine upon reaction with p‐toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH₃CN to afford either piperidines or pyrrolidines through regio‐ and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring‐opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways.     

An <Emphasis Type="Italic">AB Initio</Emphasis> Study of the Electronic and Geometric Structure of BIS-of Dipivaloylmethane With Manganese,IRON, and Cobalt

An ab initio study of the structure of Mn(thd)₂, Fe(thd)₂, and Co(thd)₂ complexes in different electronic states is carried out. Quantum chemical calculations are performed using the PC GAMESS program with relativistic effective core pseudopotentials and Gaussian valence triple-zeta basis sets. Calculation methods: DFT/ROB3LYP and CASSCF followed by the inclusion of dynamic electron correlation through multiconfiguration quasi-degenerate second order perturbation theory (MCQDPT2). All three complexes are shown to have a low-spin electronic ground state with a planar structure of the bicyclic fragment at D _2h molecular symmetry. The M—O bond is mainly ionic, and M(thd)₂ molecules can be considered as an M²⁺ cation coordinated by two negatively charged bidentate ligands.     

Opening of the Diamondoid Cage upon Ionization Probed by Infrared Spectra of the Amantadine Cation Solvated by Ar,N2, and H2O

Radical cations of diamondoids, a fundamental class of very stable cyclic hydrocarbon molecules, play an important role in their functionalization reactions and the chemistry of the interstellar medium. Herein, we characterize the structure, energy, and intermolecular interaction of clusters of the amantadine radical cation (Ama⁺, 1-aminoadamantane) with solvent molecules of different interaction strength by infrared photodissociation (IRPD) spectroscopy of mass-selected Ama⁺L_n clusters, with L=Ar (n≤3) and L=N₂ and H₂O (n=1), and dispersion-corrected density functional theory calculations (B3LYP−D3/cc-pVTZ). Three isomers of Ama⁺ generated by electron ionization are identified by the vibrational properties of their rather different NH₂ groups. The ligands bind preferentially to the acidic NH₂ protons, and the strength of the NH…L ionic H-bonds are probed by the solvation-induced red-shifts in the NH stretch modes. The three Ama⁺ isomers include the most abundant canonical cage isomer ( I ) produced by vertical ionization, which is separated by appreciable barriers from two bicyclic distonic iminium ions obtained from cage-opening (primary radical II ) and subsequent 1,2 H-shift (tertiary radical III ), the latter of which is the global minimum on the Ama⁺ potential energy surface. The effect of solvation on the energetics of the potential energy profile revealed by the calculations is consistent with the observed relative abundance of the three isomers. Comparison to the adamantane cation indicates that substitution of H by the electron-donating NH₂ group substantially lowers the barriers for the isomerization reaction.     

The structural dependence of vicinal 13C?13C coupling constants in s-cis-butane and cis-butane

The dependence of three-bond ¹³C-¹³C couplings of cis-butane and cis-butene on the valence angle, the torsional angle of the methyl groups and methyl and methylene substituents is discussed on the basis of INDO-SCPT calculations. The results support the interpretation of the experimental couplings between the bridgehead carbons of bicyclic hydrocarbons based on a multiple-path mechanism.     

Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton

Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indole moiety. Although genetic analysis has indicated that the prenyltransferase LtmE and the cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we report the reconstitution of the biosynthetic pathway for lolitrems employing a recently established genome-editing technique for the expression host Aspergillus oryzae. Heterologous expression and bioconversion of the various intermediates revealed that LtmJ catalyzes multistep oxidation to furnish the lolitrem core. We also isolated the key reaction intermediate with an epoxyalcohol moiety. This observation allowed us to establish the mechanism of radical-induced cyclization, which was firmly supported by density functional theory calculations and a model experiment with a synthetic analogue.     

Biosynthesis of Indole Diterpene Lolitrems: Radical‐Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton

Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indole moiety. Although genetic analysis has indicated that the prenyltransferase LtmE and the cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we report the reconstitution of the biosynthetic pathway for lolitrems employing a recently established genome‐editing technique for the expression host Aspergillus oryzae. Heterologous expression and bioconversion of the various intermediates revealed that LtmJ catalyzes multistep oxidation to furnish the lolitrem core. We also isolated the key reaction intermediate with an epoxyalcohol moiety. This observation allowed us to establish the mechanism of radical‐induced cyclization, which was firmly supported by density functional theory calculations and a model experiment with a synthetic analogue.     

Structure,bonding, and spectra of cyclic dithia radical cations: a theoretical study

Ab initio molecular orbital and hybrid density functional theory methods are employed to characterize the structure, bonding and properties of several cyclic dithia radical cation systems, particularly in the context of intra molecular two-center three-electron (2c-3e) bonding between two sulfur atoms. The calculated results are able to interpret the time-resolved transient optical spectra obtained from pulse radiolysis technique for these positively charged dithia systems in aqueous solution. Visualization of the appropriate molecular orbital (MO) in the systems is able to depict the presence of a 2c-3e bond between two sulfur atoms and its sigma character. Geometry optimizations of these doublet systems are carried out at restricted open shell Becke's half-and-half (BHH) nonlocal exchange and Lee-Yang-Parr (LYP) nonlocal correlation functionals (BHHLYP) with 6-311+G(d,p) basis set including solvent effects adopting Onsager's reaction field model. Hessian calculations are done at the same level to check the nature of the equilibrium geometry. Energy data are further improved by performing MP2/6-311+G(d,p) calculations on these radical cation systems. Excited-state calculations are done following configuration interaction with single-electron excitation (CIS) method and the optical transition wavelength from the highest doubly occupied molecular orbital (HDOMO) to the lowest singly occupied molecular orbital (LSOMO) is seen to correspond and match to the position of the absorption maxima (lambda(max)) obtained from the experimental spectra for all these radical cation systems in aqueous solution. These calculations are able to resolve a long-standing ambiguity in the assignment of intra molecular 2c-3e bonding in the case of the 3-methyl-2,4-dithiapentane radical cation system and to provide new insights into bonding features of this odd electron system as well as of other cyclic dithia systems studied.     

The Electronic Structure of Cubane (C8H8) as Revealed by Photoelectron Spectroscopy

High resolution He (Iα) and He (IIα) photoelectron spectra of cubane are reported. The assignments of the bands to different states of the cubane radical cation are made on the basis of ab initio STO-3G and MINDO/3 calculations, using geometries optimized within each treatment. The vibrational fine-structure observed supports the proposed assignment. An open shell MINDO/3 model for ground state cubane radical cation suggests that the Jahn-Teller distorted system fluctuates between twelve equivalent structures of C_2v-symmetry. Localized molecular orbitals derived from the STO-3G model of cubane indicate that the major feature which discriminates this molecule with respect to other hydrocarbons is the large interaction matrix element between the opposed CC-σ-orbitals of each face.     

Gas-phase nitrosation of benzene: Theoretical investigations

The structures and energetics involved in the nitrosation of benzene are explored by means of ab initio molecular orbital computations. The effects of polarization functions and electron correlation are included in these calculations. Good agreement is obtained in cases where experimental energies are available. The nitrosation of ethylene is considered as a model system to simulate the behavior of the larger nitrosyl cation (NO)⁺/benzene system. Detailed comparison reveals that careful use of such model systems can yield useful information.     

Experimental and theoretical study of 2,6-difluorophenylnitrene, its radical cation, and their rearrangement products in argon matrices.

2,6-Difluorophenylnitrene was reinvestigated both experimentally, in Ar matrices at 10 K, and computationally, by DFT and CASSCF/CASPT2 calculations. Almost-pure samples of both neutral rearrangement products (the bicyclic azirine and the cyclic ketenimine) of a phenylnitrene were prepared and characterized for the first time. These samples were then subjected to X-irradiation in the presence of CH2Cl2 as an electron scavenger, which led to ionization of the neutral intermediates. Thereby, it was shown that only the phenylnitrene and the cyclic ketenimine yield stable radical cations, whereas the bicyclic azirine decays to both of these compounds on ionization. The cyclic ketenimine yields a novel aromatic azatropylium-type radical cation. The electronic structure of the title compound is discussed in detail, and its relation to those of the iso-pi-electronic benzyl radical and phenylcarbene is traced.     

Reexamination of the C2H4F potential surface. the status of the classical 2-fluoroethyl cation: a local minimum or transition structure?

According to ab initio molecular orbital calculations carried out with full geometry optimization at the MP2/6–31G^** level, the classical 2-fluoroethyl cation, FCH₂CH₂⁺, is a transition structure for H-scrambling in CH₃CHF⁺. Single point MP4/6–31G^** calculations at the optimized geometries predict the cyclic ethylene fluoronium ion to lie 24.2 kcal mol⁻¹ above CH₃CHF⁺ and 5.4 kcal mol⁻¹ below the 2-fluoroethyl cation. ΔG‡ for ring opening of the cyclic fluoronium ion at -60° is estimated to be ca 15 kcal mol⁻¹. This barrier is largely attributable to the powerful negative fluorine hyperconjugation in the transition state as described by Hoffmann and coworkers. When electron correlation effects are ignored a qualitatively different potential surface is obtained on which the 2-fluoroethyl cation is calculated to be a local minimum separated from the stable 1-fluoroethyl cation by an H-bridged transition state.     

Energetic Properties of Rocket Propellants Evaluated through the Computational Determination of Heats of Formation of Nitrogen‐Rich Compounds

The use of ab initio and DFT methods to calculate the enthalpies of formation of solid ionic compounds is described. The results obtained from the calculations are then compared with those from experimental measurements on nitrogen‐rich salts of the 2,2‐dimethyltriazanium cation (DMTZ) synthesized in our laboratory and on other nitrogen‐rich ionic compounds. The importance of calculating accurate volumes and lattice enthalpies for the determination of heats of formation is also discussed. Furthermore, the crystal structure and hydrogen‐bonding networks of the nitroformate salt of the DMTZ cation is described in detail. Lastly, the theoretical heats of formation were used to calculate the specific impulses (I_sp) of the salts of the DMTZ cation in view of a prospective application in propellant formulations.