Can Twisted Double Bonds Facilitate Stepwise [2 + 2] Cycloadditions?

Computational studies for a series of low to high strain anti-Bredt alkenes suggest that those with highly twisted bridgehead double bonds and a small singlet-triplet energy gap may undergo facile stepwise [2 + 2] cycloadditions to furnish four membered rings. A selection of reaction substrates, including ethylene, acetylene, perfluoroethylene, and cyclooctyne are considered.

Molecular dynamics and NMR reveal the coexistence of H-bond-assisted and through-space JFH coupling in fluorinated amino alcohols.

The JFH coupling constants in fluorinated amino alcohols were investigated through experimental and theoretical approaches. The experimental JFH couplings were only reproduced theoretically when explicit solvation through molecular dynamics (MD) simulations was conducted in DMSO as the solvent. The combination of MD conformation sampling and DFT NMR spin-spin coupling calculations for these compounds reveals the simultaneous presence of through-space (TS) and hydrogen bond (H-bond) assisted JFH coupling between fluorine and hydrogen of the NH group. Furthermore, MD simulations indicate that the hydrogen in the amino group participates in both an intermolecular bifurcated H-bond with DMSO and in transmitting the observed JFH coupling. The contribution of TS to the JFH coupling is due to the spatial proximity of the fluorine and the NH group, aided by a combination of the non-bonding transmission pathway and the hydrogen bonding pathway. The experimental JFH coupling observed for the molecules studied should be represented as 4TS/1hJFH coupling.

Tetra-tert-butyl-s-indacene is a Bond-Localized C2h Structure and a Challenge for Computational Chemistry.

Whether tetra-tert-butyl-s-indacene is a symmetric D2h structure or a bond-alternating C2h structure remains a standing puzzle. Close agreement between experimental and computed proton chemical shifts based on minima structures optimized at the M06-2X, ωB97X-D, and M11 levels confirm a bond-localized C2h symmetry, which is consistent with the expected strong antiaromaticity of TtB-s-indacene.

Stereoelectronic interactions: A booster for 4 JHF transmission.

Long-range proton-fluorine coupling constants (n JHF ) are helpful for the structure elucidation of fluorinated molecules. However, their magnitude and sign can change with the relative position of coupled nuclei and the presence of substituents. Here, trans-4-tert-butyl-2-fluorocyclohexanone was used as a model compound for the study of the transmission of 4 JHF . In this compound, the 4 JH6axF was measured to be +5.1 Hz, which is five times larger than the remaining 4 JHF in the same molecule (4 JH4F = +1.0 Hz and 4 JH6eqF = +1.0 Hz). Through a combination of experimental data, natural bond orbital (NBO) and natural J-coupling (NJC) analyses, we observed that stereoelectronic interactions involving the π system of the carbonyl group are involved in the transmission pathway for the 4 JH6axF . Interactions containing the π system as an electron acceptor (e.g., σC6H6ax → π*C═O and σCF → π*C═O ) increase the value of the 4 JH6axF , while the interaction of the π system as an electron donor (e.g., πC═O → σ*CF ) decreases it. Additionally, the carbonyl group was shown not to be part of the transmission pathway of the diequatorial 4 JH6eqF coupling in cis-4-tert-butyl-2-fluorocyclohexanone, revealing that there is a crucial symmetry requirement that must be fulfilled for the π system to influence the value of the 4 JHF in these systems.

Inverse halogen dependence in anion 13C NMR.

Halogens cause pronounced and systematic effects on the 13C NMR chemical shift (δ13C) of an adjacent carbon nucleus, usually leading to a decrease in the values across the halogen series. Although this normal halogen dependence (NHD) is known in organic and inorganic compounds containing the carbon atom in its neutral and cationic forms, information about carbanions is scarce. To understand how δ13C changes in molecules with different charges, the shielding mechanisms of CHX3, CX3+, and CX3- (X = Cl, Br, or I) systems are investigated via density functional theory calculations and further analyzed by decomposition into contributions of natural localized molecular orbitals. An inverse halogen dependence (IHD) is determined for the anion series as a result of the negative spin-orbit contribution instead of scalar paramagnetic effects. The presence of a carbon nonbonding orbital in anions allows magnetic couplings that generate a deshielding effect on the nucleus and contradicts the classical association between δ13C and atomic charge.

Counterintuitive deshielding on the 13 C NMR chemical shift for the trifluoromethyl anion.

The trifluoromethyl anion (CF3 - ) displays 13 C NMR chemical shift (175.0 ppm) surprisingly larger than neutral (CHF3 , 122.2 ppm) and cation (CF3 + , 150.7 ppm) compounds. This unexpected deshielding effect for a carbanion is investigated by density functional theory calculations and decomposition analyses of the 13 C shielding tensor into localized molecular orbital contributions. The present work determines the shielding mechanisms involved in the observed behaviour of the fluorinated anion species, shedding light on the experimental NMR data and demystify the classical correlation between electron density and NMR chemical shift. The presence of fluorine atoms induces the carbon lone pair to create a paramagnetic shielding on the carbon nucleus.

Dealing with Hydrogen Bonding on the Conformational Preference of 1,3-Aminopropanols: Experimental and Molecular Dynamics Approaches.

This study expands the knowledge on the conformational preference of 1,3-amino alcohols in the gas phase and in solution. By employing Fourier transform infrared spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, density functional theory (DFT) calculations, quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) analysis, and molecular dynamics (MD), the compounds 3-aminopropan-1-ol (1), 3-methylaminopropan-1-ol (2), and 3-dimethylaminopropan-1-ol (3) are evaluated. The results show that the most stable conformation of each compound in the gas phase and in nonpolar solvents exhibited an O-H···N intramolecular hydrogen bond (IHB). Based on the experimental and theoretical OH-stretching frequencies, the IHB becomes stronger from 1 to 3. In addition, from the experimental NMR J-couplings, the IHB conformers are predominant in nonbasic solvents, representing 70-80% of the conformational equilibrium, while in basic solvents, such conformers only represent 10%. DFT calculations and QTAIM analysis in the gas phase support the occurrence of IHBs in these compounds. The MD simulation indicates that the non-hydrogen-bonded conformers are the lowest energy conformations in the solution because of molecular interactions with the solvent, while they are absent in the implicit solvation model based on density. NBO analysis suggests that methyl groups attached on the nitrogen atom affect the charge transfer energy involved in the IHB. This effect occurs mostly because of a decrease in the s-character of the LPN orbital along with weakening of the charge transfer from LPN to σ*OH, which is caused by an increase in the C-C-N bond angle.

1 J CH Coupling in Benzaldehyde Derivatives: Ortho Substitution Effect.

The natural J-coupling (NJC) method is applied to analyze the Fermi contact contribution of the NMR spin-spin coupling constant decomposing this contribution in terms of natural localized molecular orbitals. We investigated the influence of the basis set on the NJC analysis for the formyl group coupling constant (1 J CHf) of benzaldehyde derivatives. NJC and other NBO analyses, like steric and natural Coulombic energy, were chosen to explain the influence of electron-donating and electron-withdrawing groups on 1 J CHf for some substituted benzaldehydes (Me, OH, OMe, F, Cl, Br, I, and NO2). For the ortho derivatives, electronegative substituents near the C-Hf bond increase the 1 J CHf coupling. This effect could be related to an increase in formyl carbon s character and changes in the carbon and hydrogen natural charges. This indicates that the substituents in ortho have a proximity effect on 1 J CHf coupling mainly of electrostatic origin instead of the expected hyperconjugative interactions.

The Antagonist Effect of Nitrogen Lone Pair: 3 JHF versus 5 JHF.

The long-range scalar coupling constant between proton and fluorine nuclei, 5 JHF , is observed to be larger than 3 JHF in the pyrimidinyl moiety of voriconazole. A set of smaller molecules is chosen (fluorobenzene, N-methyl-2-fluoropyridine, N-methyl-3-fluoropyridine, 3-fluoropyridine, 5-pyrimidine, and 2-fluoropyridine) to evaluate the influence of the nitrogen atom in the experimental JHF values. Spectral aliased pure shift heteronuclear single quantum coherence spectroscopy (SAPS-HSQC) is applied to determine the relative sign between the JCF and JHF scalar couplings. Theoretical calculations show that the 3 JHF and 5 JHF coupling constants can be described mainly by a Fermi contact (FC) transmission mechanism. A decomposition analysis of JHF in terms of localized molecular orbital (LMO) contributions allows us to determine that the interaction involving the nitrogen lone pair (LPN) is the main reason for the larger 5 JHF compared to 3 JHF . Our analysis indicates that delocalization of LPN has a positive contribution to the long-range coupling, while a negative one is observed for 3 JHF .

The unexpected roles of σ and π orbitals in electron donor and acceptor group effects on the 13C NMR chemical shifts in substituted benzenes.

Effects of electron-donating (R = NH2) and electron-withdrawing (R = NO2) groups on 13C NMR chemical shifts in R-substituted benzene are investigated by molecular orbital analyses. The 13C shift substituent effect in ortho, meta, and para position is determined by the σ bonding orbitals in the aryl ring. The π orbitals do not explain the substituent effects in the NMR spectrum as conventionally suggested in textbooks. The familiar electron donating and withdrawing effects on the π system by NH2 and NO2 substituents induce changes in the σ orbital framework, and the 13C chemical shifts follow the trends induced in the σ orbitals. There is an implicit dependence of the σ orbital NMR shift contributions on the π framework, via unoccupied π* orbitals, due to the fact that the nuclear shielding is a response property.

Trends of intramolecular hydrogen bonding in substituted alcohols: a deeper investigation.

Intramolecular hydrogen bonding (IAHB) is one of the most important intramolecular interactions and a critical element in adopted molecular arrangements. Moreover, slight substitution in a molecule can affect its strength to a great extent. It is well established that alkyl groups play a positive role in IAHB strength. However, the effects that drive it are specific to each system. To investigate the influence of IAHB and its strength dependency on different acyclic compounds, the conformational preferences of propane-1,3-diol, 3-methoxypropan-1-ol, 3-ethoxypropan-1-ol, 3-isopropoxypropan-1-ol, 3-(tert-butoxy)propan-1-ol, butane-1,3-diol, 3-methoxybutan-1-ol, 3-methylbutane-1-diol, and 3-methoxy-3-methylbutan-1-ol were evaluated experimentally using infrared spectroscopy theoretically supported by topological and natural bond orbital analyses. The most stable conformation of each compound exhibited IAHB and these conformers are more populated in the equilibrium for all studied compounds. Experimental infrared and topological data suggest that the strength of IAHB increases for each methyl group addition. NBO analyses indicate that methyl groups in different positions related to an OH moiety affect the charge transfer energy involved in intramolecular hydrogen bonding. This occurs mostly due to an increase in the spn-hybridized lone pair (LP1O) contribution to the charge transfer , which is a result of changes in s-character and orbital energy caused by geometrical rearrangements, rehybridization, and/or electronic effects.

NMR spin-spin coupling constants: bond angle dependence of the sign and magnitude of the vicinal (3)JHF coupling.

The dependence of the magnitude and sign of (3)JHFF on the bond angle in fluoro-cycloalkene compounds is evaluated by electronic structure calculations using different levels of theory, viz. DFT, SOPPA(CCSD) and SOPPA(CC2). Localized molecular orbital contributions to (3)JHFF are analyzed to assess which orbitals are responsible for (3)JHFF and which are the most important coupling transmission mechanisms for each compound. Fluoro-ethylene is used as a model system to evaluate the dependence of the (3)JHFF coupling constant on the angle between the σCα-F and σCα'-HF vectors. Through-space and hyperconjugative transmission pathways and ring strain are identified as responsible for the opposite trend between (3)JHFF and bond angle, and for the negative signs obtained for the two molecules, respectively. One of the fluorine lone pairs, σCα'-HF, σCα-F, σCα'-Cß' bonding orbitals and the σ*Cα-F antibonding orbital are involved in the J-coupling pathways, according to analyses of pairwise-steric and hyperconjugative energies.

Effects of stereoelectronic interactions on the relativistic spin-orbit and paramagnetic components of the (13)C NMR shielding tensors of dihaloethenes.

In this study, stereoelectronic interactions were considered to explain the experimental difference in the magnitude of the known heavy-atom effect on the (13)C NMR chemical shifts in cis- and trans-1,2-dihaloethene isomers (halo = F, Cl, Br or I). The experimental values were compared to the calculated values with various DFT functionals using both the nonrelativistic approach (NR) and the relativistic approximations SR-ZORA (SR) and SO-ZORA (SO). NBO and NLMO contributions to the (13)C NMR shielding tensors were determined to assess which stereoelectronic interactions have a more important effect on the shielding tensor in each principal axis system (PAS) coordinate. These analyses associated with the orbital rotation model and the HOMO-LUMO energy gap enable rationalization of trends between cis and trans isomers from fluorine to iodine derivatives. Both paramagnetic and SO shielding terms were responsible for the observed trends. It was possible to conclude that the steric interactions between the two iodine atoms and the hyperconjugative interactions involving the halogen lone pairs (LP(X)) and πC[double bond, length as m-dash]C*, σC[double bond, length as m-dash]C* and σC-X* antibonding orbitals are responsible for the lower (13)C NMR shielding for the cis isomers of the bromine and the iodine compounds than that of the trans isomers.

Experimental and theoretical studies of intramolecular hydrogen bonding in 3-hydroxytetrahydropyran: beyond AIM analysis.

The conformational preferences of 3-hydroxytetrahydropyran (1) were evaluated using infrared and nuclear magnetic resonance spectroscopic data in solvents of different polarities. Theoretical calculations in the isolated phase and including the solvent effect were performed, showing that the most stable conformations for compound 1 are those containing the substituent in the axial and equatorial orientations. The axial conformation is more stable in the isolated phase and in a nonpolar solvent, while the equatorial conformation is more stable than the axial in polar media. The occurrence of intramolecular hydrogen-bonded O-H···O in the axial conformer was detected from infrared spectra in a nonpolar solvent at different concentrations. Our attempt to evaluate this interaction using population natural bond orbital and topological quantum theory of atoms in molecules analyses failed, but topological noncovalent interaction analysis was capable of characterizing it.

Influence of OH⋯N and NH⋯O inter- and intramolecular hydrogen bonds in the conformational equilibrium of some 1,3-disubstituted cyclohexanes through NMR spectroscopy and theoretical calculations.

The analysis of concentration effects in the (1)H NMR data of cis-3-aminocyclohexanol (ACOL) showed that its diequatorial conformer changes from 60% at 0.01 mol L(-1) to 70% at 0.40 mol L(-1) in acetone-d(6). A similar increase was also observed for the diequatorial conformer of cis-3-N-methylaminocyclohexanol (MCOL), from 32% (CDCl(3) 0.01 mol L(-1)) to 55% (CDCl(3) 0.40 mol L(-1)). The increase in solvent basicity leads to a large stabilization effect for the diequatorial conformer of both compounds too. For ACOL, it changes from 47% (ΔG(eqeq-axax)=0.06 kcal mol(-1)) in CCl(4) to 93% (ΔG(eqeq-axax)=-1.53 kcal mol(-1)) in DMSO, while for MCOL it goes from 7% (ΔG(eqeq-axax)=1.54 kcal mol(-1)) in CCl(4) to 82% (ΔG(eqeq-axax)=-0.88 kcal mol(-1)) in pyridine-d(6). These results indicate that the intramolecular hydrogen bonds (IAHB) OH⋯N and NH⋯O stabilize the diaxial conformers of these compounds in a non-polar solvent. For cis-3-amino-1-methoxycyclohexane (ACNE) and cis-3-N-methylamino-1-methoxy-cyclohexane (MCNE) no changes were observed in equilibrium with the variation of solvent polarity. These results indicate for the first time that the IAHB NH⋯O is not strong enough to stabilize the diaxial conformer of these compounds and that the conformation equilibria of the cis isomers of compounds ACOL and MCOL are influenced only by the IAHB OH⋯N. Moreover, the presence of a secondary amino group (93% of diaxial conformer in CCl(4)) leads to an IAHB OH⋯N stronger than in primary and tertiary amino-derivatives (53 and 54% of diaxial conformer, respectively) for 1,3-disubstituted cyclohexanes. Values obtained from the theoretical data through the B3LYP functional are in agreement with the experimental results and indicate that the IAHB strength that influences the conformational equilibrium of these compounds is the IAHB OH⋯N. Thus, the IAHB NH⋯O do not stabilize the diaxial conformer of the cis isomer of compounds ACNE and MCNE showing that the diequatorial conformer will always be more stable than the diaxial conformer, independent of concentration or solvent.