Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• resulting partition is illustrated in Figure 3. In accordance with previous observations, the logP values exhibit the checkmark-shape: the lipophilicity decreased with the introduction of the first polar C–F bond, and with the introduction of subsequent fluorine atoms, the lipophilicity increased due to the

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• configurations that can affect the conformation. Organofluorine chemistry offers a particular attraction here, since fluorinated molecules (e.g., 3–5) tend to adopt predictable conformations due to hyperconjugative and/or dipole–dipole interactions associated with the C–F bond [11][12][13][14][15]. Such a

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

• -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

• 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

• between the fluorine atom (or the C–F bond) and the Y group (or the C=Y bond), which has been well described by a spatial/dipolar interaction between these groups, despite a minor contribution from hyperconjugation. Thus, the fluorine Perlin-like effect shown in Table 4 supports our conclusions that

Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif

• Tetiana Bykova,
• Nawaf Al-Maharik,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2017, 13, 728–733, doi:10.3762/bjoc.13.72

• (Figure 1) [1][2][3]. The cyclohexane ring has four C–F bonds on one face, two of which are aligned 1,3-diaxial. Due to the particularly polar nature of the C–F bond, the alignment of those two bonds results in a large molecular dipole moment [4][5][6]. For the parent cyclohexane ring 1 the magnitude of

Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

• Mathew J. Jones,
• Ricardo Callejo,
• Alexandra M. Z. Slawin,
• Michael Bühl and
• David O'Hagan

Beilstein J. Org. Chem. 2016, 12, 2823–2827, doi:10.3762/bjoc.12.281

• each other in a cyclohexane ring is introduced as a new design strategy which could be applicable to the preparation of polar hydrophobic cyclohexane motifs. Keywords: aliphatic rings; C–F bond; cyclohexane conformation; difluoromethylene group; organofluorine chemistry; Introduction Selective

• incorporation of fluorine atoms is a powerful strategy for modulating the properties of organic compounds [1][2][3]. For instance, the replacement of hydrogen by fluorine is commonly practised in medicinal [4][5] and agrochemical [6][7] research programmes. The dipole moment associated with the C–F bond has

Ring-whizzing in polyene-PtL₂ complexes revisited

• Oluwakemi A. Oloba-Whenu,
• Thomas A. Albright and
• Chirine Soubra-Ghaoui

Beilstein J. Org. Chem. 2016, 12, 1410–1420, doi:10.3762/bjoc.12.135

• agreement with each other. Benzene–Ni(PR3)2 compounds have been known for some time [41]. An η2 geometry has been observed to be the precursor to C–F bond insertion for F6C6 complexes [42] and a number of theoretical studies have been carried out [43][44][45][46] which address this reaction. There are two

Copper-promoted hydration and annulation of 2-fluorophenylacetylene derivatives: from alkynes to benzo[b]furans and benzo[b]thiophenes

• Yibiao Li,
• Liang Cheng,
• Xiaohang Liu,
• Bin Li and
• Ning Sun

Beilstein J. Org. Chem. 2014, 10, 2886–2891, doi:10.3762/bjoc.10.305

• reaction and its application in the synthesis of benzo[b]furan and benzo[b]thiophene derivatives is presented starting from readily available 2-fluorophenylacetylene derivatives. The key annulation step involves the hydration of the C–F bond of 2-fluorophenylacetylene derivatives followed by an

Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines via silver triflate-catalyzed or electrophile-mediated one-pot tandem reaction

• Xiaoli Zhou,
• Meiling Liu,
• Puying Luo,
• Yingjun Lai,
• Tangtao Yang and
• Qiuping Ding

Beilstein J. Org. Chem. 2014, 10, 2286–2292, doi:10.3762/bjoc.10.238

• fluorine atoms because of the strong electronegativity, the small size, the strength of the C–F bond, and the low polarizability of the fluorine atom. Statistically, more than 20% of the pharmaceuticals and 40% of the agrochemicals contain one or more fluorine atoms. Thus, there has been considerable

Visible light photoredox-catalyzed deoxygenation of alcohols

• Daniel Rackl,
• Viktor Kais,
• Peter Kreitmeier and
• Oliver Reiser

Beilstein J. Org. Chem. 2014, 10, 2157–2165, doi:10.3762/bjoc.10.223

• developed is limited to benzylic, α-carbonyl, and α-cyanoalcohols; with other alcohols a slow partial C–F bond reduction in the 3,5-bis(trifluoromethyl)benzoate moiety occurs. Keywords: C–O bond activation; deoxygenation; photochemistry; photoredox catalysis; visible light; Introduction The dwindling

The difluoromethylene (CF₂) group in aliphatic chains: Synthesis and conformational preference of palmitic acids and nonadecane containing CF₂ groups

• Yi Wang,
• Ricardo Callejo,
• Alexandra M. Z. Slawin and
• David O’Hagan

Beilstein J. Org. Chem. 2014, 10, 18–25, doi:10.3762/bjoc.10.4

• between those H(1)···H(4) interactions relative to those with CH2 at the corner. Also if the CF2 locates at an edge this would require that a C–F bond project into the middle of the ring. The larger steric influence of the fluorine, projecting into the tightly packed arrangement of endo orientated

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

• highly-polarised C–F bond is incorporated into a nitrogen heterocycle, it can be expected to have a dramatic influence on the molecules’ physical and chemical properties [14]. The influence that fluorine can have on chemical reactivity is illustrated by considering the smallest N-heterocycles, the

• illustrates a strategy for achieving stereoselectivity in C–F bond formation. The racemic β-lactam 4b was synthesised as a single diastereoisomer from the Schiff base 79 (Scheme 11), by a Reformatsky addition followed by spontaneous cyclisation; removal of the amine protecting group under oxidative conditions

Triol-promoted activation of C–F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl)propane

• Pier Alexandre Champagne,
• Alexandre Saint-Martin,
• Mélina Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2013, 9, 2451–2456, doi:10.3762/bjoc.9.283

• C–F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bond-donating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bond-accepting ones are hindering it. However, the reaction is best run

• under highly concentrated conditions, where solvents cannot interfere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary amines or anilines to form benzylic amines in good yields. Keywords: C–F bond activation; highly concentrated

• ). Conclusion In summary, we have described that according to our previous proposed mechanism for the hydrogen bond-promoted C–F bond activation [17], simultaneous coordination of the three lone pairs of fluorine by a triol (e.g. 2) permits the nucleophilic substitution of benzylic fluorides by amines under

Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

• Holger Erdbrink,
• Elisabeth K. Nyakatura,
• Susanne Huhmann,
• Ulla I. M. Gerling,
• Dieter Lentz,
• Beate Koksch and
• Constantin Czekelius

Beilstein J. Org. Chem. 2013, 9, 2009–2014, doi:10.3762/bjoc.9.236

• findings, suggests that there are two factors determining the overall hydrophobicity of fluorinated amino acids [26]. On one hand, substitutions of hydrogen by fluorine increase the solvent accessible surface area and thus lead to an increase in hydration energy. On the other hand, the C–F bond is more

Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

• Lin Yan,
• Zhiqiang Han,
• Bo Zhu,
• Caiyun Yang,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2013, 9, 1853–1857, doi:10.3762/bjoc.9.216

• ). Keywords: allylic alkylation; asymmetric catalysis; fluorine; fluoro-β-keto esters; Morita–Baylis–Hillman carbonates; natural product; Introduction Fluorine is the most electronegative element in the periodic table, resulting in a highly polar C–F bond. This gives fluoro-organic compounds unique

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

• Magnus Liljenberg,
• Tore Brinck,
• Tobias Rein and
• Mats Svensson

Beilstein J. Org. Chem. 2013, 9, 791–799, doi:10.3762/bjoc.9.90

• PCM water solvation are depicted in Figure 5. All three structures are very similar, and the main difference between the σ-complex and TS2 is a slight elongation of less than 0.1 Å of the breaking C–F bond in TS2. An IRC-calculation showed that F leaves as F− without the assistance of explicit

• of the diffuse functions the energy of TS1 relative to the σ-complex is decreased to 0.13 kcal/mol and the energy of TS2 is increased to 6.5 kcal/mol. Consistent with the picture that diffuse functions are needed to describe the negative charge formed at the fluorine, the C–F bond is much longer

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

• revealed that the CF2 groups always occupied corner positions. This was deduced by a combination of 19F NMR, X-ray structure analysis and theory studies. Two reasons emerged for this. Firstly, if a C–F bond did project into the ring (endo), then the increased size of the fluorine atom relative to hydrogen

• 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

• study examined whether the vicinal C–F bonds prefer to adopt corner/edge or edge/edge locations of the [3333] ring system. For each diastereoisomer it emerged that one of the C–F bonds adopts a corner location. The second orientates exo to the ring. When the C–F bond projects endo into the ring, the

Prins fluorination cyclisations: Preparation of 4-fluoro-pyran and -piperidine heterocycles

• Guillaume G. Launay,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2010, 6, No. 41, doi:10.3762/bjoc.6.41

• -piperidines were investigated. The products were obtained in good yields, but only with moderate diastereoselectivity. These Prins fluorination reactions can be accelerated under microwave conditions. The study extends the Prins fluorination methodology for the generation of the C–F bond in heterocycles

• . Keywords: 4-fluoropiperidine; 4-fluoropyran; heterocycles; organo-fluorine chemistry; Prins cyclisation; Introduction Selective incorporation of the C–F bond into organic molecules can impart useful and attractive properties to performance materials [1][2][3]. To this end there are a useful but relatively

• incorporated into the product generating a C–F bond and a new stereogenic centre. Liberation of fluoride ion from BF3·OEt2 has, for example, been observed in epoxide ring opening reactions [8][9]. This was first recognised in a Prins reaction as an unexpected side reaction by Al-Mutairi et al. [10][11] and was

Chemical aminoacylation of tRNAs with fluorinated amino acids for in vitro protein mutagenesis

• Shijie Ye,
• Allison Ann Berger,
• Dominique Petzold,
• Oliver Reimann,
• Benjamin Matt and
• Beate Koksch

Beilstein J. Org. Chem. 2010, 6, No. 40, doi:10.3762/bjoc.6.40

• the preparation of caged proteins. Fluorine is the most electronegative element and has a van der Waals radius of 1.47 Å [10]. Thus, substitution of a C–H bond with a C–F bond dramatically changes the electronic properties of the given molecule but exerts only a minor steric effect [11]. Due to the

• was treated with N-(4-pentenoyloxy)succinimide and in the second step treatment with iodoacetonitrile gave the desired compound in yields ranging from 59 to 81%. Due to the strong electron-withdrawing character of the C–F bond, the CF3 substituent in the α-position in α-(Tfm)Ala influences

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

• conformational tool for the synthesis of shape-controlled functional molecules. This review will begin by describing some general aspects of the C–F bond and the various conformational effects associated with C–F bonds (i.e. dipole–dipole interactions, charge–dipole interactions and hyperconjugation). Examples

• ; stereoelectronic effects; Review General aspects of the C–F bond Fluorine is a small atom, with an atomic radius intermediate between that of hydrogen and oxygen (Table 1). The small size of fluorine means that it can be incorporated into an organic molecule as a replacement for hydrogen without dramatically

• affecting the overall molecular size. However, fluorine is the most electronegative element in the periodic table, consequently the C–F bond is highly polarised and in this sense it is a dramatic change from a C–H bond [1][2]. In the highly polarised C–F bond, the fluorine atom bears a partial negative

Three step synthesis of single diastereoisomers of the vicinal trifluoro motif

• Vincent A. Brunet,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2009, 5, No. 61, doi:10.3762/bjoc.5.61

• diastereoisomeric series of this motif. The route is a significant improvement on an earlier six step strategy. Keywords: C–F bond; organo–fluorine chemistry; stereospecific fluorination; vicinal trifluoro motif; Introduction Selective fluorination is an important strategy for the design of performance molecules

• in medicinal chemistry programmes and in organic materials [1][2]. To date arylfluorines have dominated this agenda. However molecules where the C–F bond is a constituent of a stereogenic centre are gaining in prominence, particularly as new reagents and more versatile asymmetric methods facilitate

• their syntheses [3][4]. The fluorine atom is small, with a steric impact only a little larger than hydrogen, and it is a weak hydrogen bond acceptor [4]. However the C–F bond is polar and thus interactions with nearby functional groups are largely a result of dipolar interactions rather than hydrogen

DBFOX- Ph/metal complexes: Evaluation as catalysts for enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones

• Takehisa Ishimaru,
• Norio Shibata,
• Dhande Sudhakar Reddy,
• Takao Horikawa,
• Shuichi Nakamura and
• Takeshi Toru

Beilstein J. Org. Chem. 2008, 4, No. 16, doi:10.3762/bjoc.4.16

• electrophilic fluorination represents an important and straightforward strategy for C-F bond formation at a carbon stereocenter, providing easy access to chiral fluoro-organic compounds [1][2]. Due to the significance of chiral fluoro-organic compounds, such as fluorinated quinolones [3][4] and liquid crystals

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

• Frédéric R. Leroux,
• Baptiste Manteau,
• Jean-Pierre Vors and
• Sergiy Pazenok

Beilstein J. Org. Chem. 2008, 4, No. 13, doi:10.3762/bjoc.4.13

• to methanol [46]. The geminally 1,1-difluorinated 2,3,4,6-tetra-O-acetyl-1-deoxy-D-glucopyranose (6, Figure 3) [47] exhibits unequivocally non-identical C-F bond lengths, according to crystallography. The difference of 1.5 hundredth of an Å falls in the expected range. 2,2,3,3-Tetrafluoro-2,3-dihydro

Single and double stereoselective fluorination of (E)-allylsilanes

• Marcin Sawicki,
• Angela Kwok,
• Matthew Tredwell and
• Véronique Gouverneur

Beilstein J. Org. Chem. 2007, 3, No. 34, doi:10.1186/1860-5397-3-34

• Selectfluor. These reactions proceeded with efficient transfer of chirality from the silylated to the fluorinated stereocentre. Upon double fluorination, an unsymmetrical ethyl syn-2,5-difluoroalk-3-enoic ester was prepared, the silyl group acting as an anti stereodirecting group for the two C-F bond forming

• events. Findings Asymmetric C-F bond formation continues to challenge chemists, inspiring the development of increasingly effective protocols for stereocontrolled fluorination. [1][2][3][4][5][6][7][8][9][10][11] Studies from our laboratory illustrated that allylsilanes undergo electrophilic

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

• noticed a conformational presence in α-fluoroamides [29], where the C-F bond aligns anti and planar to the amide carbonyl as illustrated in Figure 10. This adds an additional conformational constraint to these amides with a barrier to rotation around the C(CO)-C(F) bond of around 7-8 kcal mol-1. The

• preference of the C-F bond in α-fluoroamides to align anti periplanar to the carbonyl bond can be rationalized in terms of C-F bond and amide dipole relaxation as well as N-H...F hydrogen bonding [30]. The solution and solid state structures of 2,3-difluorosuccinate benzylamides 22 have been evaluated. These

Stereoselective α-fluoroamide and α-fluoro- γ-lactone synthesis by an asymmetric zwitterionic aza-Claisen rearrangement

• Kenny Tenza,
• Julian S. Northen,
• David O'Hagan and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2005, 1, No. 13, doi:10.1186/1860-5397-1-13

• fluorine at the stereogenic centre. Introduction The development of methods for the stereoselective introduction of the C-F bond, α-to a carbonyl group has been a significant and recent focus in organo-fluorine chemistry.[1][2] Most effort has involved enolate reactions with electrophilic fluorinating

• containing substrates gave higher diastereoselectivities relative to the non-fluorinated counterpart an observation which may have its origin in electronic stabilisation of one diastereoselective transition state as a consequence of the C-F bond. The aza-Claisen products where then subjected to