Bromination of endo-7-norbornene derivatives revisited: failure of a computational NMR method in elucidating the configuration of an organic structure

• Demet Demirci Gültekin,
• Arif Daştan,
• Yavuz Taşkesenligil,
• Cavit Kazaz,
• Yunus Zorlu and
• Metin Balci

Beilstein J. Org. Chem. 2023, 19, 764–770, doi:10.3762/bjoc.19.56

• temperatures yielding mixtures of addition products. The structural elucidations of the formed compounds were achieved by NMR spectroscopy. Particularly, the γ-gauche effect and long-range couplings were instrumental in assigning the stereochemistry of the adducts. However, in a recent paper, Novitskiy and

• erroneous mechanistic pathway. Keywords: bromination; computational NMR; γ-gauche effect; NMR; NOE-Diff experiments; Introduction Nuclear magnetic resonance (NMR) spectroscopy is one of the most important analytical tools used to determine the structure of organic compounds. NMR not only confirms the

• proves that there is no W arrangement between the H5exo/H6exo protons and the H7 proton. The resonance signal of the protons H2 and H3 collapsed to triplet indicating the zigzag orientation of the relevant protons (Supporting Information File 1). Structure proof using γ–gauche effect: The γ-gauche effect

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• (CnpGnpCnpGnpAnpAnpTnpTnpCnpGnpCnpG)-3' at 2 Å resolution [71]. It was found that the overall duplex structure adopted by 3'-NP DNA resembles that of an RNA-like A-form double helix. The deoxyribose ring of phosphoramidate DNA is locked in a northern (C3'-endo) conformation due to the decreased gauche effect between 4'-O and the 3

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• folding, thereby stabilizing or destabilizing particular secondary structure folds. Fluorination creates a pucker bias due to orbital interactions of the carbon–fluorine bond within the molecule, known as the gauche-effect [50]. The parent proline structure has a negligible energetic difference between

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• for E-alkenes in medicinal chemistry. Keywords: Alzheimer's disease; bioisostere; conformational analysis; gauche effect; stereoselective synthesis; Introduction Piperine (1, Figure 1) is a well-known natural product that is derived from peppercorns [1][2][3]. Many biological studies of 1 have been

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

• lipophilicity with the molecular conformation. Keywords: dipole moment; fluorinated compounds; gauche effect; herbicides; log P; Introduction Whilst in the last years the agrochemical industry has encountered a period of downturn affected by new regulations, low crop prices, biochemical resistance, among

• polar solvent (e.g. water), however, decreases the difference in energy among conformers and Igg becomes the most stable conformer in solution, i.e., a double gauche effect takes place (see data in parentheses in Figure 2). This is not surprising, since Igg has the highest dipole moment (data shown in

• conformer Igg is the most stabilized by the ΔENL term, which can be attributed to the stabilizing interactions featured in the gauche effect [14][20], due to the gauche arrangement along the two F–C–C–O pathways. The charge transfer from the filled σCH orbital to the empty σ*CF or σ*CO orbitals amounts to

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• conformation. An electron-withdrawing substituent tends to adopt an axial position due to an orbital effect called the gauche-effect (stereoelectronic effect) [67][68]. Conversely, a bulky substituent adopts an equatorial position (steric effect) [69][70]. At the same time, there has been no evidence that a

• origin of the effect is orbital (the gauche-effect) rather than through space dipolar interaction (assuming that an interaction of dipoles would be attenuated in polar solvents, which was not observed). A stabilization of certain side-chain conformers was also observed in the trifluoromethylated

• influence onto the trans/cis ratio. In contrast, the gauche-effect in fluoroprolines causes a much stronger stabilization of the C4-conformations, as this propagates into stronger effects in the trans/cis equilibrium. In addition, there is a weak but systematic modulation in the trans/cis equilibrium caused

Isolation and characterisation of irinans, androstane-type withanolides from Physalis peruviana L.

• Annika Stein,
• Dave Compera,
• Bianka Karge,
• Mark Brönstrup and
• Jakob Franke

Beilstein J. Org. Chem. 2019, 15, 2003–2012, doi:10.3762/bjoc.15.196

• of H-15 with H-12 and other protons. As an alternative, OH-14 α configuration was deduced from the chemical shifts of C-12 and C-9, which experience a strong shielding γ-gauche effect for OH-14α configurations [21]. These data indicate a relative stereochemistry of irinan B matching withanolide F (5

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

• 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

• : anomeric effect; gauche effect; NMR spectroscopy; organofluorine compounds; Introduction The active species of Ishikawa´s reagent [N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine, 1] [1] (Figure 1) has diastereotopic substituents (fluorines), which can be useful to provide conformational insights by using

• generalized anomeric effect, as well as by the fluorine gauche effect. The former corresponds to a stabilizing effect originated from the electron delocalization from the nitrogen lone pair to an antiperiplanar C–F antibonding orbital (nN → σ*C–F), similarly to that observed for some pnictogen compounds and

Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines

• Felix Scheidt,
• Christian Thiehoff,
• Gülay Yilmaz,
• Stephanie Meyer,
• Constantin G. Daniliuc,
• Gerald Kehr and
• Ryan Gilmour

Beilstein J. Org. Chem. 2018, 14, 1021–1027, doi:10.3762/bjoc.14.88

• mono-fluoromethyl unit and the C(sp3)–O bond of the ring are aligned in a synclinal relationship thereby engaging in stabilising hyperconjugative interactions with vicinal, electron-rich σ-bonds (σC–C→σ*C–F and σC–H→σ*C–O). This manifestation of the stereoelectronic gauche effect was established by X

• ; cyclisation; fluorination; gauche effect; hypervalent iodine; oxazolines; Introduction Marine and terrestrial natural product bioprospecting has established a broad spectrum of structurally complex, bioactive metabolites containing the venerable 2-oxazoline unit [1][2]. This diversity is exemplified by the

• the structure of oxazoline 2c bearing a p-NO2 group (Figure 4 and Table 2) [39]. The molecular structure reveals the expected gauche arrangement with a dihedral angle FCCO ≈ −73.4° due to σC–C→σC–F* and σC–H→σC–O* interactions. This observation is in agreement with the fluorine gauche effect

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

• Robert Szpera,
• Nadia Kovalenko,
• Kalaiselvi Natarajan,
• Nina Paillard and
• Bruno Linclau

Beilstein J. Org. Chem. 2017, 13, 2883–2887, doi:10.3762/bjoc.13.280

• blocks do not contain stereogenic C–F bonds. The vicinal-difluoride motif is known to exert conformational control through the fluorine gauche effect [14][15], and so building blocks containing this motif are of interest [16][17]. We have previously reported on the gram-scale synthesis of meso-2,3

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

• organofluorine compounds affects conformational properties, since it can induce stereoelectronic effects, such as σC–H to σ*C–F hyperconjugative interactions in case of an antiparallel oriented C–H bond. This is the origin of the so-called 'gauche effect', because electronegative C–X bonds do not participate in

• such hyperconjugative interactions and therefore often give way to the C–H bond in occupying the antiperiplanar orientation relative to the C–F bond [2][3][4][5][6]. The electrostatic fluorine gauche effect has also been introduced in cases where the partially negative fluorine interacts with a

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• previously employed catalyst 47, which worked only in organic solvent. The key component for the achievement of catalyst’s 50 catalytic ability is the known "gauche effect" of fluorine in the pyrrolidine ring, where σ*(C–F) and σ(C–H) vicinal orbitals tend to overlap [28]. For a more efficient overlap of

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

• 10.3762/bjoc.10.84 Abstract The gauche effect in fluorinated alkylammonium salts is well known and attributed either to an intramolecular hydrogen bond or to an electrostatic attraction between the positively charged nitrogen and the vicinal electronegative fluorine atom. This work reports the effect of

• phase and in implicit water through theoretical calculations. Despite the presence of σCH→σ*CF and σCH→σ*CN interactions, which usually rule the hyperconjugative gauche effect in 1,2-disubstituted ethanes, the most important forces leading to the double gauche effect (+NH3 in the gauche relationship

• -difluoroethylamine hydrochloride; gauche effect; hydrogen bonding; Introduction The conformational isomerism of alkylamines devotes interest because intramolecular effects relative to hydrocarbon analogues are affected by the electronegativity of the nitrogen atom and by the basicity of the amino group. However

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• :13.0). Keywords: catalysis; enantioselectivity; fluorine; gauche effect; organo-fluorine; Steglich rearrangement; Introduction Molecular editing using fluorine is a powerful strategy to modulate the conformation and reactivity of small molecule organocatalysts [1][2][3]. The negligible steric penalty

• pairs, such as in the case of the fluorine anomeric effect [5], to electron rich sigma bonds (σ→σ*). The stereoelectronic gauche effect in 1,2-difluoroethane is the most prominent example (1; Figure 1) [6][7][8][9]. The counterintuitive preference of vicinal fluorine substituents to adopt a gauche

• is consistent with the recently reported fluorine–NHC gauche effect [22]. The second fluorination site embeds the β-fluoroamine within the bicycle framework of the triazolium salt, thus restricting conformational freedom (e.g. 8). This later scenario was inspired by the elegant work of Rovis and co

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

• appropriately-aligned σCH orbital is able to donate electron density into the vacant σ*CF antibonding orbital. This stabilising interaction is only possible if the C–F and C–N bonds are aligned gauche to one another, and is analogous to the well-known fluorine gauche effect [24]. The importance of the rigid Cγ

The preferred conformation of erythro- and threo-1,2-difluorocyclododecanes

• Yi Wang,
• Peer Kirsch,
• Tomas Lebl,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2012, 8, 1271–1278, doi:10.3762/bjoc.8.143

• hyperconjugative interactions with the anti-periplanar C–H bonds, similar to that found in 1,2-difluoroethane in the well know gauche effect [10][11]. On the other hand, the erythro stereoisomer 5a would have a C–F bond projecting into the ring in an endo manner, if the vicinal fluorines were edge/edge located

Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

• Bruno Linclau,
• Leo Leung,
• Jean Nonnenmacher and
• Graham Tizzard

Beilstein J. Org. Chem. 2010, 6, No. 62, doi:10.3762/bjoc.6.62

• ; epoxide opening; gauche effect; organofluorine; vicinal difluoride; Introduction Selective fluorination of bioactive compounds is a widely employed strategy for the modification of their properties [1]. Fluorine atoms can be introduced to modulate the pKa of adjacent acidic and basic functional groups as

• imaging using 18F [4], and modification of high-performance materials [5]. In recent years, the vicinal difluoride motif has received increasing attention due to the conformational properties instilled by the ‘gauche effect’ [6], which results in the vicinal difluoro gauche conformation being more stable

• 11, from which it can be concluded that the gauche effect in 11 (anti) is operating in solution. Conclusion The synthesis of meso-2,3-difluoro-1,4-butanediol 3 was achieved in 5 steps from (Z)-1,4-butenediol in 40% overall yield on a multigram scale. A high-yielding (94%) monosilylation was also

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• and thus will lower the energy of the gauche conformer of 11. In contrast, in the anti conformer of 11 each σ*CF orbital is now aligned with an adjacent C–F bond, which is highly polarised and less electron releasing than a C–H bond and hence hyperconjugation does not occur. The gauche effect is only

• a subtle conformational influence compared with the dipole–dipole and charge–dipole interactions described earlier. Nevertheless, the gauche effect is very general and applies in many other systems in addition to 1,2-difluoroalkanes. For example, compounds containing F–C–C–O and F–C–C–N also

• experience this effect (12–15, Figure 1c) [9][11][12][13]. In general, more electronegative substituents give rise to stronger gauche effects. It should be noted that there are other explanations for the gauche effect in addition to the hyperconjugation argument presented above. For example, the “bent bond

The vicinal difluoro motif: The synthesis and conformation of erythro- and threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives

• David O'Hagan,
• Henry S. Rzepa,
• Martin Schüler and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2006, 2, No. 19, doi:10.1186/1860-5397-2-19

• these differed from the 2,3-difluorosuccinates. Conclusion In general the overall chain conformations of the 2,3-difluorosuccinates diastereoisomers were found to be influenced by the fluorine gauche effect. The study highlights the prospects of utilising the vicinal difluorine motif (RCHF-CHFR) as a

• difluorocompounds efficiently and particularly in a stereoselective manner. There are attractive reasons to explore this motif. It is well known that the conformation of 1,2-difluoroethane is influenced by the fluorine gauche effect, where the fluorines prefer to be gauche rather than anti to each other [1]. This

• these results have recently been communicated [18]. The study suggests that the vicinal fluorine gauche effect can have a significant influence on the conformation of the 1,2-difluorosuccinates. Results and Discussion Synthesis of erythro- and threo- 1,2-diphenyl-1,2-difluoroethanes 13 Stilbene 9 is