Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• employed as acylation reagents [1][2][3]. The strong C–F bond makes acyl fluorides relatively stable towards hydrolysis and easier to handle than other acyl halides [4][5][6][7][8]. Their reactions with nucleophiles are typically less violent than for the corresponding acyl chlorides with acyl fluorides

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• 1b. Wherein various alkyl and aryl olefins, including those that contain Lewis basic esters, carbamates and amines or α-branched moieties, may be used in efficient and exceptionally Z-selective cross-metathesis reactions [6][7][8]. A few years ago, some publications devoted to the cleavage of the C–F

• bond in butenes 1a,b have been presented in the literature. First, Crimmin et al. investigated the reaction of an aluminum(I) complex with fluoroalkenes. Unlike all the presented fluoroolefins, the reaction of the Al(I) complex with (Z)-butene 1b did not allow isolating the intermediate organoaluminum

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• . Note that, in this process, Selectfluor® is playing a key role. Indeed, using this electrophilic fluorinating source as oxidant generates a Pd(IV)(ppy)F(OAc)2 (ppy = 2-phenylpyridine) complex as intermediate. As the competitive C–F bond formation was disfavored (slow reductive elimination step), the

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

•  19D). In carbocyclic substrates the displacement of a C–F bond or ionization with a Lewis acid is difficult, but mesylates are stable and suitable for AlMe3 activation. As already mentioned, indoles are an important class of molecules with potential antidiabetic properties since they can act as GPR40

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• interest due to fluorine’s unique physical and chemical properties, such as its small size, high electronegativity, and high C–F bond dissociation energy [22][23][24]. Organofluoro compounds developed as drug molecules often display increased metabolic stability and bioavailability compared to non

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• groups, promoter, solvent and temperature has to be applied. In 1981, Mukaiyama et al. introduced glycosyl fluorides [5] as a new class of glycosyl donors [6]. The C–F bond is one of the strongest single bonds in the realm of organic compounds with a bond dissociation energy (BDE) of 570 kJ/mol [7]. Thus

• reaction was observed and mannosyl fluoride α-1a was fully recovered. Recently, Pedersen et al. have studied the vessel effect on the C–F bond activation of glucosyl fluorides [63]. They have proposed an autocatalytic glycosylation by SiF4 generated in situ form initially released HF that reacts with

• performed on the model reaction α-11 + MeOH → α-13c to elucidate the influence of SO2 on the dissociation of the glycosidic C–F bond [78] (Figure 2). Indeed, it was found that the coordination of the Lewis acidic SO2 to the fluoride (transition state TS-A≠ versus TS-A(SO2)≠) decreases the C–F bond

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

• Letcka et al., which can be seen as a strong nF→2pC interaction (Wiberg bond order of 0.53 for each C–F bond), gave additional credit to these calculations (Figure 1, bottom) [26][27][28]. The thermochemical data can also provide information on the effect of the CF3 group on the stability of the

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• disrotation at C2 and C3 during stereomutation in 1,1-difluorocyclopropanes [85]. An important feature in the fluorinated system was the stabilization of the intermediate 2,2-difluorotrimethylene radicals due to the conjugation of the radical centers with the σ*-orbital of C–F bond, which can be represented

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

• Danny Lainé,
• Vincent Denavit,
• Olivier Lessard,
• Laurie Carrier,
• Charles-Émile Fecteau,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2020, 16, 2880–2887, doi:10.3762/bjoc.16.237

• destabilize the adjacent carbocation center [41][42][43], avoiding 1,2-alkyl shift, and thus formation of byproduct 20. Similarly, the large dipole moment of the C–F bond at C2 influences the outcome of the deoxyfluorination at C4 [3]. For triflates 16 and 17, both dipoles (green arrows, Figure 3a) are

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

• . Stereoselective fluorination is an emerging strategy for controlling the conformations of organic molecules. The highly polarized C–F bond tends to align in predictable ways with adjacent functional groups, due to a combination of hyperconjugative and/or dipolar interactions [18][19][20][21]. This knowledge led

Activation of pentafluoropropane isomers at a nanoscopic aluminum chlorofluoride: hydrodefluorination versus dehydrofluorination

• Maëva-Charlotte Kervarec,
• Thomas Braun,
• Mike Ahrens and
• Erhard Kemnitz

Beilstein J. Org. Chem. 2020, 16, 2623–2635, doi:10.3762/bjoc.16.213

• 1,1,1,2,3-pentafluoropropane (HFC-245fa, HFC-245cb, and HFC-245eb) were activated through C–F bond activations using aluminium chlorofluoride (ACF) as a catalyst. The addition of the hydrogen source Et3SiH is necessary for the activation of the secondary and tertiary C–F bonds. Multiple C–F bond activations

• such as hydrodefluorinations and dehydrofluorinations were observed, followed by hydroarylation and Friedel–Crafts-type reactions under mild conditions. Keywords: aluminum fluoride; C–F bond activation; dehydrofluorination; hydrodefluorination; hydrofluorocarbons; Introduction Hydrofluorocarbons

• in part needed due to the high dissociation energy of C–F bonds, and in general, C–F activation steps are considered to be challenging [20][21][22][23][24][25][26][27]. Solid Lewis acids with a high fluoride ion affinity as catalysts are useful tools for C–F bond activation reactions since the Lewis

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

• soil sorption and bioconcentration of organic compounds. Since the C–F bond is the most polar in organic chemistry, the orientation of fluorine substituents originating from the rotation around C–C(F) bonds should affect the polarity and, consequently, the physicochemical and biological properties of

• on conformation, membrane permeation, pharmacokinetic properties, among other parameters [7]. From a conformational analysis point of view, the fluorine atom presents minimal steric effects; on the other hand, due to its high electronegativity, the C–F bond is highly polarized, which characterizes it

• conformations along the 1,2-disubstituted ethane motif, the C–C(F) bond was rotated to additionally obtain conformers Igg and Iga, and the corresponding geometries were then optimized. The resulting geometries and relative conformational energies are summarized in Figure 2. At first, we observe that the overall

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• . One exciting development in C–F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this

• fluorinated agrochemicals (Figure 2) [7][8]. Fluorine possesses some unique properties, such as the highest atomic electronegativity [9] and, in its molecular form (F2), the most positive standard reduction potential (E0) of +2.87 V [10], as predictable from its position in the periodic table. The C–F bond

• ][119][120][121][122]. There are many approaches to photosensitized fluorination that do not involve direct C–H activation, which are reviewed elsewhere [123][124][125], such as C–C bond fragmentation/C–F bond formation [126], aminofluorination of cyclopropanes [127] and decarboxylative fluorination

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• polarizability of the oxygen lone pairs due to the fluorine electronegativity. However, while D2 is a β-fluorohydrin, its fluorine is substituted at a tertiary position, with the C–F bond able to polarize the six C–H bonds of the methyl groups, which has a lipophilicity lowering effect. The electron-withdrawing

• cases, for the same fluorination motif, the cyclopropane derivatives have a lower lipophilicity compared to their acyclic equivalents. It is also useful to compare lipophilicities of acyclic and cyclopropane derivatives in which the isosterism represents conversion of a C–H and C–F bond into a C–C bond

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• characteristics of the C‒F bond [6][7] are the basis for the electronic and steric properties of the CF3 group, such as a strong electron-withdrawing (−I) effect, the accumulation of negative charge density in a relatively small volume and the low polarizability of the fluoro atoms. These and other substituent

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

• fluorination usually increases polarity of a molecule due the newly introduced polar C–F bond. A CF3 group introduces a dipole of a similar size (see Figure 2), however, due to its high molar volume it increases the hydrophobicity of a molecule [75]. The overall outcome may appear paradoxical: a CF3 group can

• diastereomers exhibited some differences. The cis-diastereomer 1 with the C–F bond pointing in the same direction as the carboxymethyl group, appeared more polar compared to the trans-isomer 2, where the direction was opposite (ΔlogPcis/trans ≈ −0.18). The same effect was observed in 4-hydroxyprolines as well

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• substituents, electron-neutral and electron-rich rings with several substitution patterns performed well. However, pyridine-based 48j resulted in a low yield. Noteworthy, the PKR of chiral enynes 48 led to a bridgehead quaternary stereocenter containing a C–F bond in a single step. Besides the intrinsic

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• established by single crystal X-ray diffraction (Figure 2). Interestingly, a study by Pattison has established that α-fluoroketones preferentially adopt a cis-conformation in polar solvents [54]. In the solid state, a dihedral angle of φ = −3.7° was observed thereby placing the C–F bond in the same plane as

Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes

• Zeguo Fang,
• Nawaf Al-Maharik,
• Peer Kirsch,
• Matthias Bremer,
• Alexandra M. Z. Slawin and
• David O’Hagan

Beilstein J. Org. Chem. 2020, 16, 674–680, doi:10.3762/bjoc.16.65

• vertical alignment (VA) LCD technology, liquid crystals with negative dielectric anisotropy are required [3]. Fluorine, as the most electronegative atom, forms stable bonds to carbon and can thus induce polarity. It is also attractive as a design feature due to the low polarizability of the C–F bond

• dielectric anisotropy by introducing the C–F bond or the dipole of a CF2 group either parallel or perpendicular to the long molecular axis. For example, in the area of negative liquid crystalline materials, Kirsch et al. have reported the synthesis of bicyclohexane and bis(cyclohexyl)ethane liquid crystals

• difluorocarbene addition to alpha-fluorostyrenes [13]. This used the extraordinary useful method for the generation of difluorocarbene from the Ruppert–Prakash (TMSCF3) reagent [14]. DFT analysis suggests the lowest energy conformer of aryl α,β,β-trifluorocyclopropane 7 orients the C–F bond perpendicular to the

Synthesis, liquid crystalline behaviour and structure–property relationships of 1,3-bis(5-substituted-1,3,4-oxadiazol-2-yl)benzenes

• Afef Mabrouki,
• Malek Fouzai,
• Armand Soldera,
• Abdelkader Kriaa and
• Ahmed Hedhli

Beilstein J. Org. Chem. 2020, 16, 149–158, doi:10.3762/bjoc.16.17

• in organic chemistry [3]. The C–F bond is highly polarized and this polarity inhibits the lone pair donation from fluorine, making this element a weak coordinator. These properties are the basis for the unique properties of perfluoroalkylated compounds such as high viscosity, high density, high

• -plane zigzag conformation [36]. Fluorine is the most electronegative element of the periodic table. This high electronegativity confers to C–F bond a large dipole moment of 1.39 D while that of C–H bond is only 0.40 D [37]. Owing to the all-trans conformation, the local dipole moments Cδ−–Hδ+ of

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• aryl fluorides [23][32]. Allylic fluorination: In 2010, Doyle and co-worker [35] developed a strategy for C–F bond formation of readily available cyclic allylic chlorides and AgF using a Pd(0) catalyst in combination with Trost’s bisphosphine ligand at room temperature (Scheme 2a). They also proved

• has been proposed. First, a bis(terpyridyl)Pd(II) complex B is oxidized by Selectfluor with turnover-limiting to obtain Pd(III) C and a Selectfluor radical cation. Then, a transfer of a F· radical from the Selectfluor radical cation to an aryl trifluoroborate occurs, forming the C−F bond and producing

• Cu-catalyzed fluorination of 2-pyridylaryl bromides was achieved by Liu and co-workers [80] through a Cu(I/III) catalytic cycle as well (Scheme 36). This method is based on the aid of an important pyridyl directing group and the final aryl C–F bond is formed after the reductive elimination of ArCu

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• , Université Laval, Québec, QC G1V 0A6, Canada 10.3762/bjoc.14.6 Abstract In recent years, the highly polar C–F bond has been utilised in activation chemistry despite its low reactivity to traditional nucleophiles, when compared to other C–X halogen bonds. Paquin’s group has reported extensive studies on the

• demonstrated that both associative and dissociative pathways operate to varying degrees, according to the nature of the nucleophile and the hydrogen bond donor. Keywords: benzylic fluorides; C–F activation; chiral liquid crystal; 2H NMR; PBLG; stereochemistry; Introduction The C–F bond is the strongest

• years, there has been an increasing interest in C–F bond activation [2], with a view to using organic bound fluoride as a leaving group in substitution reactions that typically require more activated leaving groups. Such an approach could circumvent the requirement for protecting groups in multistep

Conformational preferences of α-fluoroketones may influence their reactivity

• Graham Pattison

Beilstein J. Org. Chem. 2017, 13, 2915–2921, doi:10.3762/bjoc.13.284

• preferred for α-fluoroacetophenone, which places the C–F bond in the same plane as the C=O bond, making orbital interactions impossible. Although orbital interactions between chlorine’s lone pairs and the C=O π* orbital are expected to be weak, at least α-chloroacetophenone has a lowest energy gauche

• lone pairs and the filled C=O π-orbital. The higher polarizability of higher halogens such as chlorine and bromine may be able to reduce this repulsion, however, the tightly held, non-polarizable lone pairs of fluorine are likely to experience this repulsive effect most strongly. The shorter C–F bond

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• negative charge, with a dipole moment of 1.4 D. Finally, the monofluoroalkene has the ability to accept a hydrogen bond through the fluorine atom [9]. Geometrically, the monofluoroalkene is quite similar to the amide bond. The C=O bond of the amide is 1.228 Å, compared to 1.376 Å for the C–F bond, and the

• bond isostere [6]. Using this strategy, a mutant tripeptide containing two different peptide bond isosteres could be synthesized (Figure 3). In 2016, Konno and co-workers developed a stereoselective chromium-mediated C–F bond cleavage followed by a C–C bond formation to access (Z)-monofluoroalkenes