Reactivity of N-nitrosoamides in confined spaces

The thermal rearrangement of several N-nitrosoamides was studied by ¹H NMR in the context of reversible encapsulation. The N-nitrosoamide guests were isolated from the bulk solvent in a hydrogen-bonded dimeric host capsule which prevented their rearrangement. The guests appear to be preserved in their ground state conformations by the pressure exerted by the host. The conformations of the free and bound N-nitrosoamides are of comparable relative energies as determined by DFT calculations.     

Synthesis of macrocyclic terpenoids by intramolecular cyclization V. transannular reactions of hedycaryol isomers

Thermal rearrangement and acid-catalyzed cyclization of all possible geometrical isomers of hedycaryol were investigated. From the stereochemistry of the products, the reacting conformations were deduced. While three (E,E-, E,Z- AND Z,E-) isomers reacted through the crossed conformations, Z,Z-isomer yielded products $\text{via}$ parallel conformations. The thermal reaction at higher temperatures revealed the additional pathways involving Cope rearrangement of elemols. All possible stereoisomers of elemol were synthesized. The structure of “epielemol” has to be revised.     

Supramolecular catalysis of unimolecular rearrangements: substrate scope and mechanistic insights

A cavity-containing metal-ligand assembly is employed as a catalytic host for the 3-aza Cope rearrangement of allyl enammonium cations. Upon binding, the rates of rearrangement are accelerated for all substrates studied, up to 850-fold. Activation parameters were measured for three enammonium cations in order to understand the origins of acceleration. Those parameters reveal that the supramolecular structure is able to reduce both the entropic and enthalpic barriers for rearrangement and is highly sensitive to small structural changes of the substrate. The space-restrictive cavity preferentially binds closely packed, preorganized substrate conformations, which resemble the conformations of the transition states. This hypothesis is also supported by quantitative NOE studies of two encapsulated substrates, which place the two reacting carbon atoms in close proximity. The capsule can act as a true catalyst, since release and hydrolysis facilitate catalytic turnover. The question of product hydrolysis was addressed through detailed kinetic studies. We conclude that the iminium product must dissociate from the cavity interior and the assembly exterior before hydroxide-mediated hydrolysis, and propose the intermediacy of a tight ion pair of the polyanionic host with the exiting product.     

Recent Developments in the Stereochemistry of Cyclopropane Ring Opening

This review article deals with the stereochemistry of the following ring opening reactions: 1. Homoallylic rearrangement of secondary and tertiary cyclopropyl alcohols in the presence of electrophilic reagents, 2. The addition of carboxylic acids to vinylcyclopropanes, 3. The thermal rearrangement of vinylcyclopropanes into cyclopentenes. An account is also given of the NMR spectroscopic determination of the conformations of substituted vinylcyclopropanes.     

Synthesis of Anti-beta-substituted gamma,delta-unsaturated amino acids via Eschenmoser-Claisen rearrangement

Anti-beta-substituted gamma,delta-unsaturated amino acids have been synthesized via a novel design of the Eschenmoser-Claisen rearrangement. The rearrangement gives good isolated yields and excellent diastereoselectivity due to (Z)-N,O-ketene acetal formation and the pseudochairlike conformations of the reaction intermediates. Upon reductive hydrolysis, important novel amino acids and amino alcohols were synthesized for the first time via this methodology.     

Molecular fragmentations: Part V. Structures and energies of mass spectral fragments derived from ethyl acetate

Calculations have been made using MINDO/3 of the structures and energies of four conformations of ethyl acetate, of four isomeric forms of its molecular ion, and of all the fragment and rearrangement ions in the mass spectrum together with those of the corresponding neutral fragments.     

Thermal and photochemical transformation of conformational chirality into configurational chirality in the crystalline state

Because they crystallize in chiral conformations in which abstraction of only one of two diastereotopic gamma-hydrogen atoms is possible, salts formed between achiral keto-acids possessing the tricyclo[4.4.1.0]undecane ring system and optically pure amines undergo Norrish type II cleavage in the solid state in enantiomeric excesses as high as 95% at 98% conversion, following removal of the ionic chiral auxiliaries. Thermal enolene rearrangement of the same salts results in optical yields approximately half those observed for the photochemical reaction.     

Konformation und Circulardichroismus der Sesquiterpene vom Trichothecan-Typ und deren makrocyclischen Estern

The circular dichroism of keto derivatives with trichothecane skeleton and some of their rearrangement products has been measured. The sign (and sometimes even the magnitude) of all COTTON effects can be explained by applying the respective rules for the cyclohexanone, cyclopentanone, enone and ene-ester chromophores. Thus conformations could also be determined in those cases which did not follow unambiguously from conformational analysis. The conformation of the muconic acid moiety of the macrocyclic ring of verrucarin A is the same in dioxane solution as in the crystalline state.     

Fickle hexadienes. Manipulating the relative energies of chairlike and boatlike transition structures for the cope rearrangement

We report calculations on various hexadienes that can assume both chairlike and boatlike conformations, yet turn out (theoretically) to have transition structures for boatlike Cope rearrangement that are equal to or lower in energy than those of alternative chairlike structures. Pathways connecting boatlike and chairlike transition states in these systems also allow for unusual and facile isomerization pathways of certain strained alkenes.     

Electron impact induced fragmentation of steroidal diketones with ‘abnormal’ stereochemistry

The mass spectral fragmentations of steroidal diketones with ‘unnatural’ sterechemistry at positions 8, 9 and 14 have been examined by the use of high resolution, metastable defocusing and isotopic labeling techniques. In addition, the elucidation of fragmentation pathways was greatly facilitated by the use of the INTSUM computer program. In contrast to 14α-11-ones, where the McLafferty rearrangement is of minor importance in directing the fragmentation, it is suggested that the ketones in the present study, by virtue of their ring C flexibility, readily undergo the McLafferty rearrangement. If correct, this would represent a further example of available ground state conformations controlling fragmentation after electron impact.     

Computational Investigation of the Effect of pH on the Color of Firefly Bioluminescence by DFT

In spite of recent advances towards understanding the mechanism of firefly bioluminescence, there is no consensus about which oxyluciferin (OxyLH₂) species are the red and yellow‐green emitters. The crystal structure of Luciola cruciata luciferase (LcLuc) revealed different conformations for the various steps of the bioluminescence reaction, with different degrees of polarity and rigidity of the active‐site microenvironment. In this study, these different conformations of luciferase (Luc) are simulated and their effects on the different chemical equilibria of OxyLH₂ are investigated as a function of pH by means of density functional theory with the PBE0 functional. In particular, the thermodynamic properties and the absorption spectra of each species, as well as their relative stabilities in the ground and excited states, were computed in the different conformations of Luc. From the calculations it is possible to derive the acid dissociation and tautomeric constants, and the corresponding distribution diagrams. It is observed that the anionic keto form of OxyLH₂ is both the red and the yellow‐green emitter. Consequently, the effect of Luc conformations on the structural and electronic properties of the Keto‐(?1) form are studied. Finally, insights into the Luc‐catalyzed light‐emitting reaction are derived from the calculations. The multicolor bioluminescence can be explained by interactions of the emitter with active‐site molecules, the effects of which on light emission are modulated by the internal dielectric constant of the different conformations. These interactions can suffer also from rearrangement due to entry of external solvent and changes in the protonation state of some amino acid residues and adenosine monophosphate (AMP).     

Effect of binding and conformation on fluorescence quenching in new 2',7'-dichlorofluorescein derivatives

[structure: see text] Symmetrical and unsymmetrical 2',7'-dichlorofluorescein (DCF) derivatives have been synthesized by means of Mannich reactions and an aromatic Claisen rearrangement. NMR and fluorescence spectroscopic studies reveal the correlation between the conformations, the photoinduced electron transfer mechanism, and fluorescent intensities of these DCF derivatives. Two quenching nitrogen atoms cooperatively and reversibly suppress the fluorescence of the chromophore.     

Solution NMR Structure of a Ligand/Hybrid-2-G-Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding

Telomeric G-quadruplexes have recently emerged as drug targets in cancer research. Herein, we present the first NMR structure of a telomeric DNA G-quadruplex that adopts the biologically relevant hybrid-2 conformation in a ligand-bound state. We solved the complex with a metalorganic gold(III) ligand that stabilizes G-quadruplexes. Analysis of the free and bound structures reveals structural changes in the capping region of the G-quadruplex. The ligand is sandwiched between one terminal G-tetrad and a flanking nucleotide. This complex structure involves a major structural rearrangement compared to the free G-quadruplex structure as observed for other G-quadruplexes in different conformations, invalidating simple docking approaches to ligand–G-quadruplex structure determination.     

Structure and Chemistry of Malonylmethyl- and Succinyl-Radicals. The search for homolytic 1,2-rearrangements

Malonylmethyl radical I [· CH₂CH(COOEt)₂] and its thioester analogue II [· CH₂CH(COOEt) (COSEt)] were generated by standard photolytic and thermolytic methods from perester and bromo precursors. The structures of I and II were examined by ESR spectroscopy and found to exist in preferred conformations. However, no indication for their rearrangement by 1,2-shift of either an ethoxycarboxyl or (ethylthio)carbonyl group to the corresponding succinyl radicals III and IV , respectively, was found at temperatures below ? 40°C. At higher temperatures of up to 140°C, the search for malonylmethyl → succinyl rearrangement was examined by thorough-product analysis of the perester decomposition. There is evidence for the rearrangement of the radical I to III by photolysis and of the radical II to IV by thermolysis at 130°C in chlorobenzene to only a small extent.     

The synthesis of two diastereomeric seco-rhazinilams with opposite atropomeric chiralities

(−)-Tabersonine 4 was submitted to quaternization and Emde degradation to yield the 3,4-seco derivative 5, which was hydrolyzed and decarboxylated to the diastereomeric indolenines 8 and 9. Oxidative rearrangement of 8 and 9 yielded the two diastereomeric seco-rhazinilams (−)-10 and (+)-11, differing in the atropomeric conformations of their biarylic system. The results are discussed in the realm of oxidation and rearrangements in the aspidosperma series of indole alkaloids.     

Computational studies on glyceraldehyde and glycine Maillard reaction-II

Density-functional theory (BLYP/6-31G*) and semiempirical theory was used to study compounds related to a strained cyclic hexaalkyne that was postulated by Staab et al. as a trimeric intermediate in the copper-mediated oxidative coupling of 2,2′-diethynylbiphenyl. Among the products of this reaction is an ortho-arene cyclyne. It was found that the hexaalkyne→ortho-arene cyclyne rearrangement is quite exothermic (ca. 130 kcal/mol). Of the semiempirical methods tested, the AM1 results were closer than PM3 or MNDO to BLYP/6-31G*. For the intermediate, two conformations were found: the expected D₃-symmetric conformation and an unexpected C₂-symmetric conformation. Structures and energies of hexamethyl- and dodecamethyl-substituted analogues of the intermediate and product were also calculated at the AM1 level, in order to test whether steric effects might stabilize the intermediate, relative to the product. It was found that even very sterically crowded products were much more stable than the relevant intermediates. This suggested that the large exothermicity of the hexaalkyne→ortho-arene cyclyne rearrangement might be used to drive formation of interesting strained products. An example used to illustrate this is the rearrangement of a binaphthyl analogue of Staab's biphenyl intermediate. BLYP and AM1 calculations suggest that the rearrangement of this intermediate would be exothermic by ca. 105–110 kcal/mol, despite strain induced by formation of three [5]helicene moieties in the product.     

Simulation of phase behavior and mechanical properties of ideal interpenetrating networks

In this work microphase separation in ideal interpenetrating networks as well as its influence on the mechanical properties of the networks has been studied. Structures with long-range order in such networks have not been found to be formed; the reason for this is apparently the weak bonding (physical entanglements) between the subnetworks. The dynamics of the relaxation of interpenetrating networks with highly incompatible subnetworks has been studied and it has been found that the slow rearrangement of phase boundaries during the stretching process has a significant influence on it. Using the analysis of subchains conformations, it has been found that the increase in the stiffness of interpenetrating networks with incompatible subchains occurs due to the irregular tension of subchains related to the presence of big aggregates in the system.     

Solution NMR Structure of a Ligand/Hybrid‐2‐G‐Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding

Telomeric G‐quadruplexes have recently emerged as drug targets in cancer research. Herein, we present the first NMR structure of a telomeric DNA G‐quadruplex that adopts the biologically relevant hybrid‐2 conformation in a ligand‐bound state. We solved the complex with a metalorganic gold(III) ligand that stabilizes G‐quadruplexes. Analysis of the free and bound structures reveals structural changes in the capping region of the G‐quadruplex. The ligand is sandwiched between one terminal G‐tetrad and a flanking nucleotide. This complex structure involves a major structural rearrangement compared to the free G‐quadruplex structure as observed for other G‐quadruplexes in different conformations, invalidating simple docking approaches to ligand–G‐quadruplex structure determination.     

DNA-mediated charge transport requires conformational motion of the DNA bases: elimination of charge transport in rigid glasses at 77 K

We have proposed that DNA-mediated charge transport (CT) is gated by base motions, with only certain base conformations being CT-active; a CT-active conformation can be described as a domain, a transiently extended pi-orbital defined dynamically by DNA sequence. Here, to explore these CT-active conformations, we examine the yield of base-base CT between photoexcited 2-aminopurine (Ap*) and guanine in DNA in rigid LiCl glasses at 77 K, where conformational rearrangement is effectively eliminated. Duplex DNA assemblies (35-mers) were constructed containing adenine bridges Ap(A)nG (n = 0-4). The yield of CT was monitored through fluorescence quenching of Ap* by G. We find, first, that the emission intensity of Ap* in all DNA duplexes increases dramatically upon cooling and becomes comparable to free Ap*. This indicates that all quenching of Ap* in duplex DNA is a dynamic process that requires conformational motion of the DNA bases. Second, DNA-mediated CT between Ap* and G is not observed at 77 K; rather than hindering the ability of DNA to transport charge, conformational motion is required. Moreover, the lack of DNA-mediated CT at 77 K, even through the shortest bridge, suggests that the static structures adopted upon cooling do not represent optimum CT-active conformations. These observations are consistent with our model of conformationally gated CT. Through conformational motion of the DNA bases, CT-active domains form and break-up transiently, both facilitating and limiting CT.     

Dissociative and associative mechanisms of cope rearrangements of fluorinated 1,5-hexadienes and 2,2'-bis-methylenecyclopentanes

The effects of fluorine substitution on the Cope rearrangements of 1,5-hexadiene and 2,2'-bis-methylenecyclopentane have been examined computationally using (U)B3LYP/6-31+G(d,p) and CASPT2/6-31G(d) methodology. The calculations indicate that fluorine substituents at the hexadiene termini generally stabilize the transition states relative to the ground states of the chair conformations and destabilize pathways that occur via boat conformations, in accord with the experimental observations of Dolbier. With meso-2,2'-bis(difluoromethylene)cyclopentane, this destabilization is sufficient to favor a relatively dissociative concerted transition state resembling weakly interacting allyl radicals over a normal aromatic concerted boat transition state. This preference is due partly to an increase in the activation enthalpy for the concerted rearrangement coupled with the more favorable entropy for dissociation. In octafluoro- and decafluorohexadienes, the situation is reversed, and reaction through a cyclohexane-1,4-diyl is favored. Even in the octafluoro system with no radical stabilizing substituents at C(2) and C(5), the preference of fluorine for sp(3) centers causes reaction via the cyclohexane-1,4-diyl. In establishing methodology for this study, the conformations of 1,2-difluoroethane and 1,1,2,2-tetrafluoroethane were also examined thoroughly by the B3LYP method using three basis sets.