Conformational Analysis Explores the Role of Electrostatic Nonclassical CF···HC Hydrogen Bonding Interactions in Selectively Halogenated Cyclohexanes.

The conformational equilibria of selectively halogenated cyclohexanes are explored both experimentally (VT-NMR) for 1,1,4,-trifluorocyclohexane 7 and by computational analysis (M06-2X/aug-cc-pVTZ level), with the latter approach extending to a wider range of more highly fluorinated cyclohexanes. Perhaps unexpectedly, 7ax is preferred over the 7eq conformation by ΔG = 1.06 kcal mol-1, contradicting the accepted norm for substituents on cyclohexanes. The axial preference is stronger again in 1,1,3,3,4,5,5,-heptafluorocyclohexane 9 (ΔG = 2.73 kcal mol-1) as the CF2 groups further polarize the isolated CH2 hydrogens. Theoretical decomposition of electrostatic and hyperconjugative effects by natural bond orbital analysis indicated that nonclassical hydrogen bonding (NCHB) between the C-4 fluorine and the diaxial hydrogens at C-2 and C-6 in cyclohexane 7 and 9 largely accounts for the observed bias. The study extended to changing fluorine (F) for chlorine (Cl) and bromine (Br) at the pseudoanomeric position in the cyclohexanes. Although these halogens do not become involved in NCHBs, they polarize the geminal -CHX- hydrogen at the pseudoanomeric position to a greater extent than fluorine, and consequent electrostatic interactions influence conformer stabilities.

Autobench V1.0: Benchmarking Automation for Electronic Structure Calculations.

This work reports on new software for automatic conformer energy benchmarking calculations for flexible molecules. The software workflow consists of four parts: conformational search, preoptimization, optimization, and frequency calculations at a higher level and last calculations using several theoretical levels. The software was written to be user-friendly and versatile to be used by nonexperts in computational chemistry. Any theoretical levels available in either Gaussian 16 or ORCA 5 may be applied in the benchmarking study. The workflow will automatically run conformational search calculations and deal with conformers that converge to the same minimum and those that show a negative frequency. At the end of the workflow, the user will have the mean absolute deviations and the most accurate method/DFT functional and basis set in comparison to the benchmark to be applied for the molecular system of interest. Case examples are given at the end of the paper that may help users to get insight into the software's main features.

One-pot organocatalyzed synthesis of tricyclic indolizines.

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.

Contribution of Hyperconjugation and Inductive Effects to the Pseudo-anomeric Effect in 4-Substituted Methoxycyclohexanes.

The importance of electrostatic nonconventional hydrogen bonds (NCHBs) to the pseudo-anomeric effect of 4-substituted methoxycyclohexanes is evaluated using theory [natural bond orbital (NBO)] to deconvolute electrostatic from other contributing effects. There is an interesting interplay between σCH → σCX* hyperconjugation and the electropositive charge on 3,5-axial hydrogens (Hax). In essence, better σCX* (or πCO*) acceptors increase the charge on 3,5-CHax, which in turn strengthens Cδ+Hax···Î´-OMe NCHB interactions.

Chiral Ligands in Hypervalent Iodine Compounds: Synthesis and Structures of Binaphthyl-Based λ3 -Iodanes.

Several novel binaphthyl-based chiral hypervalent iodine(III) reagents have been prepared and structurally analysed. Various asymmetric oxidative reactions were applied to evaluate the reactivities and stereoselectivities of those reagents. Moderate to excellent yields were observed; however, very low stereoselectivities were obtained. NMR experiments indicated that these reagents are very easily hydrolysed in either chloroform or DMSO solvents leading to the limited stereoselectivities. It is concluded that the use of chiral ligands is an unsuccessful way to prepare efficient stereoselective iodine(III) reagents.

There and back again: the role of hyperconjugation in the fluorine gauche effect.

The origin of the fluorine gauche effect has been debated for decades and recently different interpretations have been raised in the scientific community as new computational methods emerged and were applied to rationalize 1,2-difluoroethane (DFE) gauche preference. In this context, we revisited 1,2-difluoroethane (DFE) and its chlorine and bromine derivative conformational preferences through a comparative approach: the conformational behavior and hyperconjugative, steric and electrostatic contributions for the internal rotational barrier of DFE were compared with several analogue backbones, such as peroxides, disulfides and ammonia boranes. By using the Natural Bond Orbital (NBO) analysis it was found that hyperconjugation is the driving force of the conformational preference in DFE and its chlorine and bromine analogues. Electrostatics was found to be negligible and steric effects played a minor role in general, but are important in ClCH2CH2Cl and BrCH2CH2Br to counterbalance gauche stabilization by hyperconjugation and for the preference of the anti conformer.

The contribution of non-classical CHaxOC hydrogen bonds to the anomeric effect in fluoro and oxa-methoxycyclohexanes.

In this theory study we demonstrate the dominance of non-classical 1,3-diaxial CHaxOC hydrogen bonds (NCHBs) dictating a 'pseudo' anomeric effect in selectively fluorinated methoxycyclohexanes and also influencing the axial preference in the classical anomeric exhibitor 2-methoxytetrahydropyran, a phenomenon which is most often described as a consequence of hyperconjugation. Analogues of methoxycyclohexane where ring CH2's are replaced by CF2 can switch to an axial preference and theory methods (NBO, QTAIM, NCI) indicate the dominance of 1,3-CHaxOMe interactions over hyperconjugation. For 2-methoxytetrahydropyran, it is revealed that the global contribution to the anomeric effect is from electrostatic interactions including NCHBs, not hyperconjugation, although hyperconjugation (nO→σ*CO or nO→σ*CC) remains the main contributor to the exo-anomeric phenomenon. When two and three ether oxygens are introduced into the ring, then both the NCHB interactions and hyperconjugative contributions become weaker, not stronger as might have been anticipated, and the equatorial anomers progressively dominate.

Through space JFH spin-spin coupling constant transmission pathways in 2-(trifluoromethyl)thiophenol: formation of unusual stabilizing bifurcated CFHS and CFSH interactions.

Given its importance and the possibility of organic F to participate in hydrogen bonds (H-bonds), the understanding of its behavior as a H-bond acceptor with different donors is crucial. The interest in organofluorine compounds and the works related to the study of the participation of this atom in non-covalent interactions is constantly growing. Following recent studies in this subject, we evaluated the existence of two bifurcated intramolecular interactions, a bifurcated CFHS H-bond in the cis conformer of 2-trifluoromethylthiophenol and an unusual, bifurcated CFSH interaction in the trans conformer. The JFH spin-spin coupling constant (SSCC) was evaluated for 2-trifluoromethylthiophenol both experimentally by 1H and 19F NMR and theoretically using the natural bond orbitals (NBO), the quantum theory of atoms in molecules (QTAIM) and the non-covalent interactions (NCI) framework. Although both interactions are crucial for the stabilization of the conformer geometries, the observed positive JFH spin-spin coupling constant (SSCC) is mainly resultant from the trans conformer, which has a large calculated positive SSCC, and is transmitted through steric interactions involving the F lone pairs and the σSH bonding orbital.

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds.

Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral (R)-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to (R)- over (S)-muscone was also computationally confirmed for muscone and fluorinated (R)-muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane α-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. The binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure-activity relationship model.

Room Temperature Coupling of Aryldiazoacetates with Boronic Acids Enhanced by Blue Light Irradiation.

A visible-light-promoted photochemical protocol is reported for the coupling of aryldiazoacetates with boronic acids. This photochemical reaction shows great enhancement compared to the same protocol performed in the absence of light. Except for a few cases, the room temperature coupling in the dark (thermal process) generally does not work. When it does, it is likely to also involve free carbenes as key intermediates. Alternatively, photochemical reactions show a broad scope, can be performed under air and tolerate a wide variety of functional groups. Reaction-evolution monitoring, DFT calculations and control experiments have been used to evaluate the main aspects of this intricate mechanistic scenario. Biologically active molecules Adiphenine, Benactyzine and Aprophen have been prepared as examples of synthetic applications.

Fluorine-Induced Pseudo-Anomeric Effects in Methoxycyclohexanes through Electrostatic 1,3-Diaxial Interactions.

We report counter-intuitive axial preferences in non-stereochemically biased, selectively fluorinated methoxycyclohexanes. These pseudo-anomeric effects are apparent when electronegative CF2 groups are placed at the C-2, C-4 and C-6 positions of the cyclohexane ring to render the C-3/5 axial hydrogen atoms electropositive. The electrostatic interaction between these axial hydrogen atoms and the -OMe oxygen is stabilising. The effect is explored using high-level ab initio and DFT calculations in the framework of NBO, QTAIM and NCI analysis across a range of derivatives, and experimentally (19 F{1 H}-NMR at -80 °C) for some illustrative examples. The effect is significant in energy terms for a weak interaction, and illustrates a new stereoelectronic aspect attributed to selective fluorine substitution in organic chemistry.

Origin of the Diastereoselectivity of the Heterogeneous Hydrogenation of a Substituted Indolizine.

In this work, the stereoselective heterogeneous hydrogenation of a tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto-enol tautomerism under kinetic control has been proposed as the source of diastereoselectivity.

The preferred geometry of hydroperoxides is the result of an interplay between electrostatic and hyperconjugative effects.

Steric, electrostatic and hyperconjugative effects were evaluated in the natural bond orbital framework as candidate sources of the preferred geometry of hydroperoxides. Stabilising 1,2-δ+H-δ-O electrostatic interactions and nO → σ*OR hyperconjugative interactions were found to be the driving force for the preferred anticlinal or perpendicular geometries, respectively. There is an interesting interplay between these two effects: when one increases, the other decreases. On the other hand, steric effects showed negligible contributions to the conformational behaviour of the studied molecules. Also, HO-OR bond dissociation energy appeared to be dependent on RO˙ radical stability, which is governed by hyperconjugation.

Intramolecular H-Bond Is Formed in 2-Fluorophenol and 2-Fluorothiophenol, but It May Not Be the Main Pathway of the JFH Coupling Constant Transmission.

The intramolecular CF···HX (X = O or S) H-bond and JFH spin-spin coupling constants (SSCCs) in 2-fluorophenol and 2-fluorothiophenol were investigated experimentally by 1H and 19F NMR and theoretically in the framework of the natural bond orbital analysis. In contrast with recent findings from the literature, the results obtained in this work showed that an intramolecular H-bond is formed in the cis conformers and that it has an electrostatic origin. Such an intramolecular electrostatic H-bond is the interaction that rules the conformational preferences on these compounds. Moreover, the natural J-coupling analysis indicated that the JHF SSCC in 2-fluorophenol has its origin on LP(F)/σOH steric interactions and should be labeled as 4TSJHF. On the other hand, the analogue SSCC for 2-fluorothiophenol has its origin on the intramolecular H-bond LP(F) → σSH* hyperconjugative interaction and should be described as a 1hJFH SSCC.

Conformational signature of Ishikawa´s reagent using NMR information from diastereotopic fluorines.

The active species of the Ishikawa´s reagent [N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine] is a fluorinating hexafluoropropylamine used to convert alcohols into alkyl fluorides. On the other hand, it is also an example of model compound useful to probe conformational preferences using spectroscopic information from diastereotopic fluorines. Moreover, the possibility of experiencing both the generalized anomeric and gauche effects makes the Ishikawa´s reagent an ideal choice to study the governing stereoelectronic interactions of the conformational equilibrium of organofluorine compounds. The conformational equilibrium of the Ishikawa´s reagent was analyzed using NMR 3 J H,F coupling constant data in different solvents, since the orientation of the diastereotopic fluorines relative to H-2 and F-2 changes with the medium. In nonpolar cyclohexane solvent, the preferred conformation experiences a weaker steric and electrostatic repulsion. The conformational behavior changes in the more polar pyridine solution, where the double fluorine gauche effect takes place, since F-2 is preferably gauche to both diastereotopic fluorines. An analysis of the rotation around the N-C(F2) bond indicates the manifestation of anomeric interactions (n N → σ*C-F), which can be demonstrated by means of 19F chemical shifts. The results were rationalized with the aid of theoretical calculations and natural bond orbital (NBO) analysis, allowing for the evaluation of competing steric, electrostatic and hyperconjugative interactions.

Infrared Fingerprints of nN → σ*NH Hyperconjugation in Hydrazides.

An earlier study demonstrated that hyperconjugation operates in hydrazides by analyzing the N-H stretching mode in gas phase infrared (IR) spectroscopy, and then observing two very distinct bands corresponding to isolated isomers experiencing or not the nN → σ*N-H electron delocalization. The present work reports a chemical method to obtain insight on the hyperconjugation in hydrazide derivatives from solution IR spectroscopy. The analogous amides did not show a νN-H red-shifted band, as the electron donor orbital in the above hyperconjugative interaction does not exist. In addition, the effect of electron withdrawing groups bonded to a nitrogen atom, namely the trifluoroacetyl and the methanesulfonyl groups, was analyzed on the conformational isomerism and on the ability to induce a stronger hyperconjugation in the resulting compounds.

Hyperconjugation Is the Source of Helicity in Perfluorinated n-Alkanes.

Hyperconjugative, steric, and electrostatic effects were evaluated as possible sources of the helicity in linear perfluorinated alkanes through analysis of natural bond orbitals and classical electrostatics. Contrary to previous rationalizations, which indicate dominating steric or electrostatic effects, this analysis indicates that hyperconjugative stabilization through σCC →σ*CF interactions are the underlying driving force for the origin of the observed helicity in perfluoroalkanes.

Inter- and intramolecular CF···C=O interactions on aliphatic and cyclohexane carbonyl derivatives.

Weak inter- and intra- molecular C(δ+)F(δ-)···C(δ+)=O(δ-) interactions were theoretically evaluated in 4 different sets of compounds at different theoretical levels. Intermolecular CH3F···C=O interactions were stabilizing by about 1 kcal mol(-1) for various carbonyl containing functional groups. Intramolecular CF···C=O interactions were also detected in aliphatic and fluorinated cyclohexane carbonyl derivatives. However, the stabilization provided by intramolecular CF···C=O interactions was not enough to govern the conformational preferences of compounds 2-4.

Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones.

The CF2 group is incorporated into specific positions within the lactone ring of the natural musk lactone, (12R)-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The approach is taken as it was anticipated that CF2 groups would dictate corner locations in the macrocycle and limit the conformational space available to the lactone. Three fluorine containing lactones are prepared by organic synthesis. One (8) has CF2 groups located at the C-6 and C-9 positions, another (9) with CF2 groups at the C-5 and C-9 positions, and a third (10) with a CF2 group at C-8. Two of the fluorine containing lactones (8 and 10) were sufficiently crystalline to obtain X-ray crystal structures which revealed that the CF2 groups do adopt corner locations. All three lactones were subject to computational analysis at the B3LYP-D3/6-311+G** level to assess the relative energies of different conformers. In all cases, the global minima and most of the lowest energy minima have squared/rectangular geometries and located the CF2 groups at the corners. The lowest energy structures for 8 and 10 closely approximated the observed X-ray structures, suggesting good convergence of theory and experiment in determining relevant low energy conformations. All three compounds retained a pleasant odour suggesting the rings retained sufficient conformational flexibility to access relevant olfactory conformations.

Understanding the conformational behaviour of Ac-Ala-NHMe in different media. A joint NMR and DFT study.

The conformational behaviour of Ac-Ala-NHMe was studied in the gas-phase and in solution by theoretical calculations (B3LYP-D3/aug-cc-pVDZ level) and experimental (1)H NMR. The conformational preferences of this compound were shown to result from a complex interplay between the strengths of possible intramolecular hydrogen bonds, steric interactions, hyperconjugation, entropy effects and the overall dipole moments. The Ac-Ala-N(Me)2 derivative was studied in addition, to design a system akin to Ac-Ala-NHMe, but with disrupted intramolecular hydrogen bonds involving the -NHMe group, mimicking the effect of polar protic solvents.