To allow a comparison with the specific rotations of R-(+)-5-methylenenorbornene (1) and R-(+)-norbornenone (2) we performed calculations at the LC-wPBE/aug-cc-pVTZ level for the imines (5a and 5b) derived from norbornenone and also for their protonated derivative (6). In accord with our results for simpler systems, the specific rotations increase in the order of 1 < 5 < 2 ≈ 6. In addition, the specific rotation of the protonated ketone was calculated and found to be considerably larger than that for 2 or 6. These rotations were found to be linearly dependent on the Hirshfeld charges at the carbon of the exocyclic double bond. This leads to the conclusion that charge transfer from the endocyclic double bond to the π* MO of the exocyclic double bond is an important component of the process that leads to the optical activity of these compounds.

The ground states of unsaturated molecules with Cs symmetry have separate σ and π molecular orbitals. This makes it possible to separately calculate the σ and π Hirshfeld populations and to analyze the effect of structural changes in more detail. A number of types of compounds have been studied: vinyl derivatives, 1-substituted hexatrienes, phenyl derivatives, and six-membered ring heterocycles. The results are shown as plots of changes in population vs atoms. The σ and π components vary widely, depending on π conjugation, σ inductive effects, and σ/π polarization. When an electron withdrawing group is attached to an alkene carbon, significant σ density is transferred to it, and to compensate π density is transferred to the substituent. Such interactions are similar to those found when a carbonyl or other ligands are attached to a metal.

The chirality derived from the interaction between two double bonds (C═C and C═X where X ═ CH2, NH, NH2+, O and S) across a methylene group has been examined in some detail at the B3LYP/aug-cc-pVTZ level. The rotamers of these formally achiral molecules that lead to large calculated specific rotations are those that allow overlap between the pair of double bonds, and the rotation is increased when the distance between them is decreased. Although the large specific rotation of unconjugated enones such as norbornenone is usually attributed to a magnetic transition dipole arising from an n–π* interaction of the carbonyl group, it has been found that large rotations may also be found with some conformations of unconjugated dienes such as 1,4-pentadiene. In the relative orientations of the double bonds that lead to large optical rotations, the pair of p–π orbitals are oriented so that they can interact leading to an electric transition dipole, while at the same time they are somewhat twisted with respect to each other allowing a significant magnetic transition dipole Other information was obtained by studying 2-propene-1-imine and its conjugate acid. The former gives only a small increase in optical rotation as compared to pentadiene. However, protonation at N leads to a large increase in optical rotation. This suggests that lone pairs have little effect on rotation, whereas the change in electronegativity has a large effect.

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

The rotameric conformations of the phenyl ring in both the axial and the equatorial conformers of phenyl substituted 1,3-dioxanes and tetrahydropyrans are compared with those of the corresponding phenylcyclohexanes at the MP2/6-311+G* level. The compounds with an axial phenyl commonly adopt a conformation in which the plane of the aromatic ring is perpendicular to the benzylic C–H bond. However, axial 5-phenyl-1,3-dioxane adopts a “parallel” conformation that allows an ortho hydrogen to be proximate to the two ring oxygens, leading to attractive CH···O interactions. Stabilizing Coulombic interactions of this sort are found with many of the oxygen-containing six-membered rings that were investigated.

The conformational preference of a variety of 2,2-diaryl-1,3-dioxanes bearing remote substituents on the phenyl rings has been studied via equilibration of configurationally isomeric 2,2-diaryl-cis-4,6-dimethyl-1,3-dioxane epimers, X-ray crystallography, 1H NOESY analysis, and B3LYP/6-311+G* calculations. When the aryl ring bears a remote electron-withdrawing substituent, the isomer having both the higher dipole moment and the electron-withdrawing group in the equatorial phenyl ring and/or an electron-donating group in the axial ring has the lower energy. These results differ from the conclusions reported in a previous study of similar systems. The conformational energy differences of para-substituted 2,2-diaryl-1,3-dioxanes are linearly related to the Hammett σ values with a slope (ρ) of 0.6. In addition, there is a trend toward longer bond lengths between the C(2) ketal center and the aryl ring as the electron-withdrawing nature of the para-substituent is increased. Electrostatic interactions, rather than a hyperconjugative anomeric effect, appear to be responsible for the conformational behavior of such molecules.

The oxidation of primary amines using a stoichiometric quantity of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in CH2Cl2–pyridine solvent at room temperature or at gentle reflux affords nitriles in good yield under mild conditions. The mechanism of the oxidation, which has been investigated computationally, involves a hydride transfer from the amine to the oxygen atom of 1 as the rate-limiting step.

The properties and reactions of compounds in which the O of dimethyl ether or acetone has been replaced by NH, PH, or AsH have been studied computationally using CBS-QB3, CBS-APNO, G4, and W1BD. The properties include the bond dissociation energies and ionization potentials, and the reactions include those with with protons, methyl cations, and lithium cations. The effect on keto–enol equilibria also was examined. In all cases there was good agreement with the available experimental data. The agreement between these methods suggests that the least computationally costly model (CBS-QB3) should be of general use in studying organic compounds. The double-bond dissociation enthalpies of CH2═XHn were linearly related to those of the corresponding CH3–XHn+1 single bonds with a slope of 2.5. With the exception of C–C, the order corresponded to the electronegativity of X, suggesting that the differences are largely determined by internal Coulombic interactions. The differences in the electronegativities of the heteroatoms are largely responsible for the differences in the properties and reactions. Oxygen has a significantly higher electronegativity than the others, and as a result, the oxygen-substituted compounds are often different than the others.

Bond dissociation enthalpies can exhibit dramatic variations resulting from substituent effects. These variations result from changes in electronic structure that accompany bond dissociation. We have studied bond dissociation enthalpies (BDEs) at the W1BD level of theory for a series of RX–H compounds where X = CH2, NH, O, PH, and S. The substituents, R, included H, H3C, H2N, HO, F, H2P, HS, and Cl. The experimentally available BDEs were reproduced in a very satisfactory fashion. Most of the substituent effects could be related to a conjugative interaction in the two-center three-electron systems in the radicals formed by H abstraction. Comparisons of isoelectronic species demonstrate the important roles that variations in electronegativity and hybridization can play in determining BDEs. The OH and SH BDEs were linearly related, and the same was found with N–H and P–H BDEs. The relative effects of H2P and HS as substituents, in contrast to H2N and HO, could be related to the need to promote a 3s electron to 3p before H2P can participate in π-bonding. We must also include electronegativity differences to account for the observed transfer of a sulfur lone pair to an oxygen but the absence of the reverse process.

The enantioselective deprotonation of N,N-diisopropy-1-methylcyclopropanecarboxamide (2) with i-PrLi-(−)-sparteine has been studied at theoretical levels up through B3LYP/6-311+G*. Thirty-six conformationally flexible intermediate complexes involving i-PrLi–(−)-sparteine and 2 were located via geometry optimizations The lowest energy complex would lead to abstraction of the pro-S hydrogen from 2, and several higher energy complexes would lead to loss of the pro-R hydrogen. The lowest energy complex was found to have the lowest activation energy leading to loss of the pro-S hydrogen of 2 as observed experimentally. The results demonstrate that the conformations of the N,N-diisopropyl groups in the amide moiety of 2 have a large effect on the enantioselectivity of the lithiation

Bond dissociation enthalpies (BDEs) can exhibit dramatic variations resulting from substituent effects. The remarkable range of experimental OH bond dissociation enthalpies have been reproduced using CBS-APNO calculations with very good accuracy, so we have employed these calculations to extend the available BDE data. The effect on these BDEs of lone pairs on the atom adjacent to oxygen shows that conjugation in the product radicals is the most important interaction leading to the wide range of values. The BDE’s were found to be linearly related to both the spin density at the radical center and to the change in X–O bond order in going from X–O–H to X–O·.

The reaction of ketones with organolithium reagents generally proceeds by addition of the organometallic to the electrophilic carbon of the C═O group to give the lithium salt of a tertiary alcohol. The seemingly analogous reaction of thioketones with organolithiums is a fundamentally different process: such reactions typically afford a variety of products, and addition of the organolithium to carbon of the C═S group to give a thiol is a relatively unimportant component. Reactions of the stable thioketone, adamantantanethione (1), with several alkyllithiums (MeLi, n-BuLi and t-BuLi) in a variety of solvents have been studied in the first comprehensive investigation of the reactions of organolithiums with a representative alkyl-substituted thione. Reactions of 1 with n-BuLi or t-BuLi afforded 2-adamantanethiol (2) as the major product. In an effort to explain the marked difference in behavior of ketones and thioketones in reactions with organolithiums, transition states for both the addition and reduction reactions have been located at the B3LYP/6-311+G* level using acetone and thioacetone as model substrates. The transition states for the addition of dimeric MeLi to the C═O and C═S carbons of acetone and thioacetone were significantly different as a result of the small bond angles preferred by divalent sulfur, and this accounts for the much slower addition to a C═S carbon vis-à-vis a C═O group. Transition states for reduction of acetone and thioacetone by EtLi were similar, but the greater exothermicity of the reduction of the thioketone results in an earlier transition state and lower activation energy for this process than that for the reduction of a ketone. The possible role of radical-mediated processes in this chemistry is also discussed.

The enthalpies of reduction of carbonyl compounds and hydrogenation of alkenes have been calculated at the HF, B3LYP, M06, MP2, G3, G4, CBS-QB3, CBS-APNO, and W1BD levels and, in the case of the first four methods, using a variety of basis sets up to aug-cc-pVTZ. The results are compared with the available experimental data, and it is found that the compound methods are generally more satisfactory than the others. Large basis sets are usually needed in order to reproduce experiments. Some C–C bond hydrogenolysis reactions also have been examined including those of bicycloalkanes and propellanes. In addition, the dimerization of the remarkably strained bicyclo[2.2.0]hex(1,4)ene was studied. The reaction forming a pentacyclic propellane was calculated to have ΔH = −57 kcal/mol, and the cleavage of the propellane to give a diene had ΔH = −71 kcal/mol. The strain energies of these compounds were estimated.

The reactions of alkyllithiums with ketones and thioketones proceed in fundamentally different ways. Whereas alkyllithiums add to the carbonyl carbon of ketones to give tertiary alcohols, the reaction with thioketones proceeds to give secondary thiols by reduction of the CS group. Transition states for the addition and reduction reactions of acetone and thioacetone in ethereal solution have been located and the computed activation free energies are in agreement with the observed behavior of ketones and thioketones in reactions with alkyllithiums.

The reactions and properties of a series of chalcogen-containing compounds (CH3)2X and (CH3)2C═X, where X = O, S, and Se, were studied computationally at the CBS-QB3 level to examine the differences among these molecules. The reactions and properties investigated include the double bond dissociation energy, the ionization potential, the interaction energies with a series of acids including a proton, CH3+, Li+, MeLi, and MeOH, and the enolization energies of the (CH3)2C═X species. The effect of substituting the O of acetamide with S or Se also was studied. The changes that result from these reactions were examined via changes in structure and changes in charge distribution using the Hirshfeld charges.

Whereas cis-substituted alkenes are normally significantly less stable than the trans-isomers, there is a group of 1-substituted propenes (X = F, OMe, Cl, Br, SMe) where the cis-isomers are the more stable. The calculated structures show that there is steric repulsion with the cis-isomers. However, this is overcome by attractive Coulombic interactions when X = F or OMe and by attractive dispersive interactions when X = Cl or Br. It was possible to calculate the magnitude of the latter term via the summation of the appropriate MP2 pair energies. The calculated and observed energy differences could be reproduced by a summation of steric, electrostatic, and dispersive interactions.

The reaction of benzoyl chloride with methanol catalyzed by pyridine is 9 times more rapid than is the same reaction with thiobenzoyl chloride. The difference in reactivity, as well as the dealkylation reactions that occur when the reaction of thiobenzoyl chloride is catalyzed by bases such as Et3N, can be understood in terms of the charge distributions in the intermediate acylammonium ions. The reaction of PhNCO with ethanol occurs at a much higher rate (4.8 × 104) than that of PhNCS, corresponding to a difference in activation free energies for the additions of 6 kcal/mol. Transition states for each of these reactions were located, and each involves two alcohol molecules in a hydrogen bonded six-membered ring arrangement. Information concerning differences in reactivity was derived from analysis of Hirshfeld atomic charge distributions and calculated hydrogenolysis reaction energies.

The structures of the four lower energy sparteine complexes were examined at several theoretical levels including B3P86/6-31G∗ and B3P86/6-311+G∗. The transition states for interconverting two pairs of conformers were determined using the synchronous transit-guided quasi-Newton procedure. Complexes with lithium hydride and propyllithium also were examined. The bidentate complexes formed from conformer 1b and propyllithium had two conformations with essentially the same energy. This may account for the low enantioselectivity observed in the reaction of alkyllithium–sparteine complexes with carbonyl compounds.