Theoretical investigations of the transition structures of additions and cycloadditions reveal details about the geometries of bond-forming processes that are not directly accessible by experiment. The conformational analysis of transition states has been developed from theoretical generalizations about the preferred angle of attack by reagents on multiple bonds and predictions of conformations with respect to partially formed bonds. Qualitative rules for the prediction of the stereochemistries of organic reactions have been devised, and semi-empirical computational models have also been developed to predict the stereoselectivities of reactions of large organic molecules, such as nucleophilic additions to carbonyls, electrophilic hydroborations and cycloadditions, and intramolecular radical additions and cycloadditions.

No abstract

Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington’s disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.

Unlike alpha-amino acids, peptides formed from beta-amino acids (beta-peptides) display stability toward enzymatic degradation and may form turns and helices with as few as four residues. Because both the C alpha and C beta of the beta-amino acid may bear substituents, a large number of beta-amino acids can be synthesized. Beta-peptides form various well-defined secondary structures, including 14-helix, 12-helix, 10/12-helix, 10-helix, 8-helix, turn structures, sheets, and hairpins. For all of these reasons, beta-amino acids have been increasingly used as building blocks for molecular design and pharmaceutical applications. To explain the conformational features of beta-peptides, several quantum mechanics and molecular dynamics studies that rationalize the observed conformational features have been reported. However, a systematic account that unifies various factors critical to the conformational features is still lacking. In this Account, we present a detailed analysis of the conformational features of various beta-peptides. We start by studying the basic local conformational features of beta-peptides using di- and tripeptide models. Then, various secondary structures of unsubstituted beta-peptides with differing numbers of residues are investigated using a repeating unit approach to derive the intrinsic backbone conformational features. We find that the 10/12-helix is intrinsically most stable for the beta-peptide backbone. The 14-helix, 12-helix, and 10-helix structures have similar stabilities for beta-peptide backbones of four to six residues. The substituent effects on the stabilities of beta-peptide secondary structures are then analyzed. Combined with the substituent effect and the intrinsic backbone preferences, all experimental observations of secondary structure formation can be understood. For example, the 10/12-helix is favored for like-beta(2)/beta(3)-peptides, unlike-beta(3)/beta(3)-peptides, and beta(3)/beta-hGly-peptides because these substitution patterns do not cause steric problems for the 10/12-helix. Beta(3)-peptides, beta(2)-peptides, and beta (2,3)-peptides favor the 14-helix because the substituents in these peptides benefit the 14-helix the most but significantly destabilize the 10/12-helix. Because the 10/12-helix is intrinsically favored and has two favorable positions in each residue for substituents, many more hybrid beta-peptides are predicted to exist in this secondary structure, which suggests the need for further experiments. These results are valuable for determining the best use of these building blocks in the design of well-structured molecules with desirable chemical functions.

Cyclooctapyrroles such as 1–3 tend to form during the condensation of dipyrrolic units if cyclization to cyclotetrapyrroles is hindered for conformational reasons. These macrocycles are chiral and might afford interesting complexes with metal ions. Their most intriguing feature is their unusual figure‐eight conformation.

Phase space matching between two plasma-accelerator (PA) stages and between a PA and a traditional accelerator component is a critical issue for emittance preservation of beams accelerated by PAs. The drastic differences of the transverse focusing strengths as the beam propagates between different stages and components may lead to a catastrophic emittance growth in the presence of both finite energy spread and lack of proper matching. We propose using the linear focusing forces from nonlinear wakes in longitudinally tailored plasma density profiles to provide exact phase space matching to properly transport the electron beam through two such stages with negligible emittance growth. Theoretical analysis and particle-in-cell simulations show how these structures may work in four different scenarios. Good agreement between theory and simulation is obtained.

No abstract

Unimolecular and bimolecular methane eliminations of TiMe4 have been studied using ab initio molecular orbital theory. Geometry optimizations were performed with the 3-21G and HW3 (equivalent to the 6−31G*) basis sets. The energies were further evaluated with the MP2/HW3 calculations. We predict a high activation energy for unimolecular methane elimination but a low activation energy for bimolecular methane elimination. For Ti(CH2CMe3)4, neopentane elimination through α- and γ-hydrogen abstractions has been studied with the 3-21G basis set. We predict an intrinsic preference for α-hydrogen abstraction over γ-hydrogen abstraction. This preference is enhanced by the bulkiness of the alkyl ligands.