Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• stereoelectronic effects such as hyperconjugation and electrostatic attraction/repulsion. These fluorine-derived conformational effects have been exploited to control the shapes, and thereby enhance the properties, of a wide variety of functional molecules including pharmaceutical agents, liquid crystals

• available to mix with any nearby filled orbital in a process known as hyperconjugation, and any molecular conformation in which such mixing can occur, will be stabilised [5][6][7]. Putting all these concepts together, it is possible to conceive of a process whereby a conformationally flexible lead compound

• compared to the non-fluorinated stearic acid 12 (Figure 3) [26]. If two fluorines are introduced into the middle of an alkyl chain in a 1,2-pattern, several competing factors arise that can influence the molecular conformation [27]. One factor is hyperconjugation: conformations in which the σ*C–F orbitals

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• and nonbonding interactions for the halogen at C4. Finally, density functional theory (DFT) calculations corroborate the preference of talose analogues to adopt a 4C1-like conformation and a natural bonding orbital (NBO) analysis demonstrates the effects of hyperconjugation from C–F antibonding

• in a chloroform solution, using the polarizable continuum model (PCM) [75]. A natural bonding orbital (NBO) analysis was performed to study the effects of hyperconjugation from C–F antibonding orbitals [76]. First, dipole moments, enthalpy and Gibbs free energy differences between 1C4 and 4C1 chair

• exception being bromine). Dipole moments for the 4C1 structures are 2 Debye larger than for 1C4 structures, making them substantially more stable in chloroform. Both chair structures have multiple C–F bonds in gauche arrangements which are stable due to hyperconjugation: there is donation from C–H bonding

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• -Lewis (electron delocalization) contributions, 17 and 19 were favored by a delicate equilibrium between weak repulsion and substantial stabilization due to hyperconjugation. Conversely, structures such as 9 and 10 experienced minimal steric effects but were inadequately stabilized by electron

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• hyperconjugation via bending the exocyclic methyl group such that the formal p-orbital at C3 no longer aligns with the C2–C7 bond results in the 6/6/6-tricyclic C3 tertiary cation B2+, which is 13.0 kcal mol−1 higher in energy. In principle, either A2+ or B2+ could be deprotonated to form products. A similar

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• differences among alkenes. As demonstrated in the case of methylcyclopentene (Figure 1), the nucleophilicity of the exo-double bond is higher compared to the internal double bond. The higher energy of exo-alkenes compared to internal alkenes is well known and attributed to a less-effective hyperconjugation of

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• hyperconjugation determines whether the reaction proceeds in a stepwise or concerted manner. The second interesting aspect of the biosynthesis of variexenol B is that the biosynthetic pathway involves an intermediate with an exomethylene group. A terpene with an exomethylene group as a starting material is rare

• carbocation are strongly influenced by hyperconjugation. In particular, C–C bonds containing a secondary cation are shortened to about 1.45 Å, showing a slight double bond character. On the other hand, in intermediates such as IM2a and IM2b, which have cation–π interactions, the surrounding bonds are hardly

• affected by hyperconjugation (C9–C10: 1.54 Å, C10–C11: 1.54 Å, C11–C1: 1.57 Å). We have also done a comparative analysis of the charge distribution in scenarios with and without cation–π interactions. In cases where the interaction is absent, the cationic character at C10 is pronounced. Conversely, in the

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• and co-workers explained the formation of all-cis-2,4,6-trisubstituted THPs with the help of density functional theory (DFT) and stated that in the presence of an external nucleophile, the stabilization of the carbocation intermediate is favored through hyperconjugation [28]. The vacant p-orbital of

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• (Figure 1, top). A second stabilizing interaction was also found and came from hyperconjugation of the CF3 substituent, involving interactions between the empty 2pC orbital with the πCF3 FO (−5.2 kcal⋅mol−1). In 2018, spectroscopic evidence for the generation of the first observable fluoronium ion 1 by

• hyperconjugation and/or fluorine lone pair interaction, resulting in a certain degree of a positive charge of one fluorine atom. Interestingly, at least one phenyl substituent was required to allow the ionization of the starting alcohols into the corresponding carbenium ions. When the aromatic substituent was

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

• Daniela Rodrigues Silva,
• Joyce K. Daré and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2020, 16, 2469–2476, doi:10.3762/bjoc.16.200

• term overcomes the stabilization from hyperconjugation interactions (ΔENL), and classical electrostatic and steric interactions are the main factors governing conformational preferences of penoxsulam (I). It is worth mentioning that the structure of penoxsulam in the biological environment is already

• average of the gauche and anti-conformers), and b) predicted log P (milog P). Second order perturbation energy E(2) of the main hyperconjugation interactions (in kcal mol–1) computed at the ωB97X-D/6-311G(d,p) level of theory. Experimental log P, dipole moment (μ, in Db), and predicted log P of

Isolation and structure determination of a tetrameric sulfonyl dilithio methandiide in solution based on crystal structure analysis and ⁶Li/¹³C NMR spectroscopic data

• Jürgen Vollhardt,
• Hans Jörg Lindner and
• Hans-Joachim Gais

Beilstein J. Org. Chem. 2020, 16, 2057–2063, doi:10.3762/bjoc.16.172

• , electrostatic interaction with and charge polarization by the positively charged sulfur atom [56] and silicon atom [57], and negative nC–σ*SPh hyperconjugation [56][58]. The anions of (2a)4·(THF)6 and (2a)6·Li2O·(THF)6 adopt conformations around the carbon sulfur bond, which would allow for stabilization by

• negative hyperconjugation. Density functional theory and natural bond order calculations of dilithio methandiides of type II [32][43] suggest that the two lone pairs at the dianionic carbon atom of (2a)4·(THF)6 and (2a)6·Li2O·(THF)6 are perhaps located in an sp2 hybridized orbital and p orbital. However

• . Their anion is stabilized by electrostatic interaction, polarization, and negative nC-σ*SR hyperconjugation, with electrostatic interaction as dominating mechanism [56][58]. The lithio methanides 1 are monomeric or dimeric in THF solution and the solid state, depending on Lewis basic ligands of the

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• , partially due to the hyperconjugation of an oxygen lone pair with an antibonding C–F orbital, and partially to the steric hindrance of the -CF3 group [6][7]. These interactions result in a relative conformational flexibility, where the -OCF3 group can rotate between the two sides of the aromatic ring

The cyclopropylcarbinyl route to γ-silyl carbocations

• Xavier Creary

Beilstein J. Org. Chem. 2019, 15, 1769–1780, doi:10.3762/bjoc.15.170

• . Computational studies support a carbocation intermediate with an unusually long Si–C bond, indicative of increased demand for Si–C hyperconjugation due to the electron-withdrawing group. With the exception of the phenyl substitution, the chemistry of trans-derivatives 14 is quite different since these

Strong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of cis-2-halocyclohexylamines

• Camila B. Francisco,
• Cleverton S. Fernandes,
• Ulisses Z. de Melo,
• Roberto Rittner,
• Gisele F. Gauze and
• Ernani A. Basso

Beilstein J. Org. Chem. 2019, 15, 818–829, doi:10.3762/bjoc.15.79

• the hyperconjugative interactions that influenced the equilibrium. The σC–H → σ*C–X hyperconjugation and the interactions involving the LPX counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong

• preference for the ea conformer in cis-2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects. Keywords: conformational equilibrium; cyclohexane derivatives; dynamic NMR; hyperconjugation; principal component

• halogen size. Instead, the equilibrium is influenced by solute–solvent hydrogen bonding with the hydroxy group. Besides the classical effects, interactions such as hyperconjugation has been pointed out as relevant in several studies involving cyclohexane derivatives [4][12][15][16][17][18][19][20]. Since

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

• Laize A. F. Andrade,
• Lucas A. Zeoly,
• Rodrigo A. Cormanich and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2019, 15, 506–512, doi:10.3762/bjoc.15.44

• this solvent is similar to that observed in cyclohexane solution. Thus, further discussion will consider only cyclohexane and pyridine solvents. The generalized anomeric effect (due to the nN → σ*C–F hyperconjugation) can be explored for assertion of the C–N–C–F dihedral angle, which contributes to

Conformational impact of structural modifications in 2-fluorocyclohexanone

• Francisco A. Martins,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2017, 13, 1781–1787, doi:10.3762/bjoc.13.172

• bonding, hyperconjugation, electrostatic and steric effects. While the gauche effect, originated from hyperconjugative interactions, does not appear to cause some preferences for the axial conformation of organofluorine heterocycles, more classical effects indeed rule the conformational equilibrium of the

• -fluorocyclohexanone; hyperconjugation; Introduction Organofluorine compounds are of special interest in materials, pharmaceutical and agricultural sciences, as the C–F bond is the most polar bond in organic chemistry, which can be useful in the design of performance organic molecules [1]. A fluorine substituent in

• interaction with the carbonyl oxygen or by electron delocalization (hyperconjugation) involving the good electron acceptor π*C=O orbital. For example, 2-fluorocyclohexanone in the gas phase exists predominantly in the axial conformation, but the equatorial form is more stable in solution [18]. In a previous

Conformational study of L-methionine and L-cysteine derivatives through quantum chemical calculations and ³J_HH coupling constant analyses

• Weslley G. D. P. Silva,
• Carolyne B. Braga and
• Roberto Rittner

Beilstein J. Org. Chem. 2017, 13, 925–937, doi:10.3762/bjoc.13.94

• most stabilized ones by hyperconjugation, such as the conformers 1-Ib and 2-Va. In this way, the NBO investigation shows that not only is a specific interaction the responsible for the observed conformational preferences for the compounds 1 and 2, but an interplay between hyperconjugation and steric

• not play a major role in the stability of the conformers of 3 and 4. Also analogously to 1 and 2, the conformational preferences observed for the conformers of the N-acetylated derivatives result from an interplay between steric repulsion and hyperconjugation. Conclusion In summary, the use of quantum

Regiochemistry of cyclocondensation reactions in the synthesis of polyazaheterocycles

• Patrick T. Campos,
• Leticia V. Rodrigues,
• Andrei L. Belladona,
• Caroline R. Bender,
• Juliana S. Bitencurt,
• Fernanda A. Rosa,
• Davi F. Back,
• Helio G. Bonacorso,
• Nilo Zanatta,
• Clarissa P. Frizzo and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 257–266, doi:10.3762/bjoc.13.29

• isomeric product 9b (see structures in the Supporting Information File 1). Additionally, it was observed that the nitrogen atom farthest from the substituent is the most nucleophilic. The better conjugation of methyl (hyperconjugation effect) and chlorine (+M effect) substituents in the para-position could

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• (steric and electrostatic) and attractive non-Lewis-type (hyperconjugation) contributions, the main factor governing the conformational stabilization of isoflurane comes from the more classical steric and dipolar interactions, likewise sevoflurane reported earlier [17]. It has been proposed that

Investigation of the role of stereoelectronic effects in the conformation of piperidones by NMR spectroscopy and X-ray diffraction

• Cesar Garcias-Morales,
• David Ortegón-Reyna and
• Armando Ariza-Castolo

Beilstein J. Org. Chem. 2015, 11, 1973–1984, doi:10.3762/bjoc.11.213

• hyperconjugation, which is related to the anomeric effect (effect where a heteroatomic substituent adjacent to a heteroatom within a cyclohexane ring prefers the axial orientation instead of the equatorial) [6][7][8][9][10][11][12]. Moreover, stereoelectronic effects have been related to the stabilization of

• carbanions [13][14], carbocations [15][16][17][18], and free radicals [19][20][21] which has been explained by negative (nX→σ*C–Y) or positive hyperconjugation (σC–Y→π* or p). Hyperconjugation is commonly described as the interaction between electronic orbitals where one filled orbital (donor) interacts with

• orbital (donor) with another unfilled orbital (acceptor) can be observed several bonds away from the orbitals. This effect is classified as hyperconjugation (electronic delocalization placing a σ-bridge between a donor and an acceptor orbital, Figure 2a), homohyperconjugation, considered the result of the

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

Probing multivalency in ligand–receptor-mediated adhesion of soft, biomimetic interfaces

• Stephan Schmidt,
• Hanqing Wang,
• Daniel Pussak,
• Simone Mosca and
• Laura Hartmann

Beilstein J. Org. Chem. 2015, 11, 720–729, doi:10.3762/bjoc.11.82

• , which is in good agreement with our results. The increased grafting reactivity of MA can be explained by the substituent on the double bond. The methyl group of MA may activate the double bond due to hyperconjugation. In addition, the activation energies for polymerization of MA is lower than for AA [19

Conformational analysis of 2,2-difluoroethylamine hydrochloride: double gauche effect

• Josué M. Silla,
• Claudimar J. Duarte,
• Rodrigo A. Cormanich,
• Roberto Rittner and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2014, 10, 877–882, doi:10.3762/bjoc.10.84

• with both fluorine atoms) in 2 are the Lewis-type ones. Particularly, electrostatic interactions are operative even in water solution, where they should be significantly attenuated, whereas hyperconjugation and hydrogen bond have secondary importance. Keywords: conformational analysis; 2,2

• -fluoropiperidinium hydrochloride (F and N with gauche arrangement) is dependent on hyperconjugation, and not only due to F···HN+ hydrogen bond and/or electrostatic attraction between the electronegative fluorine with the positively charged nitrogen [6]. However, introduction of an additional 2-fluorine atom in that

• interactions, such as steric effects and dipolar (electrostatic) interactions. On the other hand, non-Lewis-type interactions refer to electron delocalization from filled to empty orbitals, such as hyperconjugation. Indeed, the σCH→σ*CF hyperconjugative interaction has been found to be the main factor

Direct and indirect single electron transfer (SET)-photochemical approaches for the preparation of novel phthalimide and naphthalimide-based lariat-type crown ethers

• Dae Won Cho,
• Patrick S. Mariano and
• Ung Chan Yoon

Beilstein J. Org. Chem. 2014, 10, 514–527, doi:10.3762/bjoc.10.47

• radicals 18 are stabilized by an hyperconjugation-type overlap of high energy σC-Si orbitals with half-filled p-orbitals on the donor atoms. This feature causes α-trialkylsilyl-substituted electron donors to have comparable low oxidation potentials. In addition, the odd electron and positive charge

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• example, Raines and co-workers found that (4R)-fluoroproline 12 adopts a Cγ-exo ring pucker (Figure 4), in contrast with natural proline 11 which has a more flexible pyrrolidine ring [23]. The increased rigidity of 12 was explained by a stabilising hyperconjugation phenomenon (Figure 4), in which an

• -exo ring pucker of 12 was demonstrated in spectacular fashion: Raines and co-workers showed that the thermal stability of collagen was increased when 12 was incorporated in place of collagen’s naturally-present (4R)-hydroxyproline residues [25]. This hyperconjugation effect has also been exploited in

• reaction (15→17) with only moderate enantioselectivity [26]. This was ascribed to the flexibility of the pyrrolidine moiety in the enamine intermediate 16. In contrast, the fluorinated catalyst 14 has a relatively strong (1.5 kcal/mol) preference for an endo pucker, stabilised by hyperconjugation, and this

Elucidation of the regio- and chemoselectivity of enzymatic allylic oxidations with Pleurotus sapidus – conversion of selected spirocyclic terpenoids and computational analysis

• Verena Weidmann,
• Mathias Schaffrath,
• Holger Zorn,
• Julia Rehbein and
• Wolfgang Maison

Beilstein J. Org. Chem. 2013, 9, 2233–2241, doi:10.3762/bjoc.9.262

• as well as in the model system 11B-R3 helps to stabilize the radical further, mainly by hyperconjugation. In total, both substituent effects result in a rather low C–H bond-dissociation enthalpy of 79.5 kcal/mol at CBS-QB3 level of theory (74.9 kcal/mol B3LYP/6-31+G**, Table 2). Compared to the other

• BDH298 values are more subtle and might be referred to additional steric strain imposed by a change in hybridization of the carbon atom from sp3 to sp2 upon radical formation and hyperconjugation effects (Table 2). Correlating the experimental observations with the computational results, one can deduce

• in 11-R3 by the adjacent oxygen and hyperconjugation lead to a rather low BDH of 74.9 kcal/mol (B3LYP/6-31+G**). Biocatalytic allylic oxidation of theaspirane (1) with lyophilisates of PSA. Only one enantiomer of racemic compounds is shown. Intramolecular silyl modified Sakurai reaction to