The Fluorine Gauche Effect in Catalysis - ACS Publications - American

Article Cite This: Acc. Chem. Res. 2018, 51, 1701−1710

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Informing Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in Catalysis Marialuisa Aufiero and Ryan Gilmour*

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Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany

CONSPECTUS: The axioms of stereoelectronic theory constitute an atlas to navigate the contours of molecular space. All too rarely lauded, the advent and development of stereoelectronic theory has been one of organic chemistry’s greatest triumphs. Inevitably, however, in the absence of a comprehensive treatise, many of the field’s pioneers do not receive the veneration that they merit. Rather their legacies are the stereoelectronic pillars that persist in teaching and research. This ubiquity continues to afford practitioners of organic chemistry with an abundance of opportunities for creative endeavor in reaction design, in conceiving novel activation modes, in preorganizing intermediates, or in stabilizing productive transition states and products. Antipodal to steric governance, which mitigates destabilizing nonbonding interactions, stereoelectronic control allows welldefined, often complementary, conformations to be populated. Indeed, the prevalence of stabilizing hyperconjugative interactions in biosynthetic processes renders this approach to molecular preorganization decidedly biomimetic and, by extension, expansive. In this Account, the evolution and application of a simple donor−acceptor model based on the fluorine gauche effect is delineated. Founded on reinforcing hyperconjugative interactions involving C(sp3)−H bonding orbitals and C(sp3)−X antibonding orbitals [σC−H → σC−X*], this general stratagem has been used in conjunction with an array of secondary noncovalent interactions to achieve acyclic conformational control (ACC) in structures of interest. These secondary effects range from 1,3-allylic strain (A1,3) through to electrostatic charge-dipole and cation−π interactions. Synergy between these interactions ensures that rotation about strategic C(sp3)−C(sp3) bonds is subject to the stereoelectronic requirement for antiperiplanarity (180°). Logically, in a generic [X−CH2−CH2−Y] system (X, Y = electron withdrawing groups) conformations in which the two C(sp3)−X bonds are synclinal (i.e., gauche) are significantly populated. As such, simple donor−acceptor models are didactically and predictively powerful in achieving topological preorganization. In the case of the gauche effect, the low steric demand of fluorine ensures that the remaining substituents at the C(sp3) hybridized center are placed in a predictable area of molecular space: An exit vector analogy is thus appropriate. Furthermore, the intrinsic chemical stability of the C−F bond is advantageous, thus it may be considered as an inert conformational steering group: This juxtaposition of size and electronegativity renders fluorinated organic molecules unique among the organo-halogen series. Cognizant that the replacement of one fluorine atom in the difluoroethylene motif by another electron withdrawing group preserves the gauche conformation, it was reasoned that βfluoroamines would be intriguing candidates for investigation. The burgeoning field of Lewis base catalysis, particularly via iminium ion activation, provided a timely platform from which to explore a postulated f luorine−iminium ion gauche effect. Necessarily, activation of this stereoelectronic effect requires a process of intramolecularization to generate the electron deficient neighboring group: Examples include protonation, condensation to generate iminium salts, or acylation. This process, akin to substrate binding, has obvious parallels with enzymatic catalysis, since it perturbs the conformational dynamics of the system [synclinal-endo, antiperiplanar, synclinal-exo]. This Account details the development of conformationally predictable small molecules based on the [X−Cα−Cβ−F] motif through a logical process of molecular design and illustrates their synthetic value in enantioselective catalysis.

1. INTRODUCTION ... In my opinion, there is a problem that is central to organic chemistry alone and in which biologists cannot help us. We all agree... that the emphasis in synthetic research is the synthesis of properties, and not just compounds.

Fluorine is inimitable in its ability to modulate the structural and electronic properties of organic molecules.3 Grounded in a unique combination of modest steric occupancy (rvdw = 135 pm) and high electronegativity (χ = 4),4 fluorine remains an Received: May 4, 2018 Published: June 12, 2018

Albert Eschenmoser1,2 © 2018 American Chemical Society

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DOI: 10.1021/acs.accounts.8b00192 Acc. Chem. Res. 2018, 51, 1701−1710

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Accounts of Chemical Research indispensable tool for molecular editing in the medicinal,5,6 agrochemical7 and catalysis8 research disciplines. The conspicuous under-representation of fluorine in the rich tapestry of halogenated natural products9 further underscores the potential of organofluorine compounds in generating new materials with specifically engineered properties. A competent bioisostere for both H and OH,10 fluorine can be exploited as an electronically matched bioisostere of the hydroxyl group [OH → F], or to induce localized partial charge inversion when substituted for hydrogen [Hδ+ → Fδ‑].11 In the arena of natural product chemistry, modulating and augmenting bioactivity can often be achieved through single site fluorination in remarkably complex architectures.12 This aspect of organofluorine chemistry is inextricably linked to the stability of the C(sp3)−F bond: This is at variance with the remaining members of the organohalogen series. Fluorine’s inimitability, however, is most pronounced as a subtle conformational steering group. Electronegative elements lower the energies of the MOs to which they contribute, endowing the C(sp3)−F bond with a low-lying antibonding orbital (σ*C−F). Fluorine’s minimal steric demand mitigates steric override and allows this orbital to engage in stabilizing hyperconjugative interactions with a plenum of donors.13 These range from nonbonding electron pairs, in the case of the fluorine anomeric effect,14 through to more elaborate interactions with vicinal electron withdrawing groups.15 Often in the latter case, the β-substituent carries a proximal charge such that the dominant conformer is a manifestation of synergistic stereoelectronic and electrostatic interactions. A compelling argument for the strategic application of fluorine in conformational design is the gauche effect in 1,2-difluoroethane (Figure 1).16 Despite having been

Comparative crystallographic analyses of 1,2-difluoroethane (ϕ ≈ 60°) and 1,2-diiodoethane (ϕ ≈ 180°) by Lenz and coworkers beautifully demonstrated the unique juxtaposition of size and electronegativity that distinguishes fluorine from other halogens.18 Dipole effects are another logical consequence of the intrinsic polarity of the C−F bond, and are particularly effective in achieving structural preorganization in peptides.19 Collectively, molecular editing with fluorine allows a number of phenomena to be exploited for acyclic conformational refinement.20 The bond rotational profile of ethane provided the template from which this research program was derived.21 In a report by Pophristic and Goodman, the 3 kcal·mol−1 barrier that partitions the staggered and eclipsed rotamers was attributed to a combination of hyperconjugative and electrostatic interactions, in addition to exchange repulsion.22 In a striking departure from the classic steric interpretation, this model reiterates the importance of stereoelectronic contributions in governing structure. This important milestone is the subject of an excellent essay by Schreiner.23 Logically, the donor−acceptor interaction between the bonding orbital (σC−H) and antibonding orbital (σC−H*) in ethane would be enhanced by lowering the energy of the acceptor orbital (σC−H → σC−H* versus σC−H → σC−F*). In acyclic systems, the consequence of H to F substitution is immediately evident from the comparative bond rotational profiles of ethane and 1,2-difluoroethane (Figure 2). While

Figure 2. Energy profile diagram for C−C bond rotation for ethane (red) and 1,2-difluoroethane (green). DFT level of theory (TPSS-D3/ def2-TZVP).

hyperconjugation is frequently invoked to rationalize the conformational behavior of these systems, a recent study by Thacker and Popelier proposed that 1,3 C···F electrostatic polarization interactions underpin gauche stability in 1,2difluorethane.24 In both cases, the eclipsing interactions (H/ H and H/F) generate a rotational barrier of ca. 3 kcal·mol−1. However, in 1,2-difluoroethane, the gauche conformers are energetically favored over the anti on account of σC−H → σC−F* interactions (ca. 1 kcal·mol−1). Interestingly, eclipsing fluorine interactions significantly augment this barrier such that the ethane “rotor” becomes more of a “pendulum” in 1,2difluoroethane (ca. 7 kcal·mol−1). For the purposes of achieving acyclic conformational control in functional small molecules, the introduction of the [X−Cα−Cβ−F] motif offers the possibility to hinder rotation about strategically important C(sp3)−C(sp3) bonds without introducing a dominant steric bias.

Figure 1. Fluorine gauche effect in 1,2-difluoroethane.

first observed around the same time as the celebrated anomeric effect,17 the gauche effect has been less prominently employed in structural chemistry despite sharing a common stereoelectronic foundation (n → σ* and σ → σ*, respectively). In 1,2-difluoroethane, two reinforcing hyperconjugative interactions between the electron rich C(sp3)−H and C(sp3)−F bonds [σC−H → σ*C−F] generate a distinctive syn-clinal (gauche) orientation around the FCCF dihedral angle (ϕ ≈ 60°). This is favored by around 1 kcal·mol−1 relative to the corresponding anti arrangement, and is not observed in related 1,2-dihalogenated ethanes due to augmented steric volume. 1702


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Accounts of Chemical Research Evidence of the [X−Cα−Cβ−F] unit inducing extreme conformational changes in cyclic systems is evident from Snyder and Lankin’s elegant structural work on fluorinated piperidines.25−27 Protonation generates a conformation in which the fluorine substituents are placed in a quasi-axial orientation, such that the system is stabilized by both hyperconjugative and electrostatic interactions due to the proximal charge (Figure 3).

This strategy would complement the rich body of literature describing the effects of fluorination in cyclic organocatalyst scaffolds (Figure 5). Fluorine introduction has featured

Figure 3. Comparison of steric and (stereo)electronic locking in sixmembered rings.

In acyclic systems, the generality of the fluorine gauche effect has been firmly established. Replacement of one fluorine atom by an electron deficient substituent preserves the phenomenon provided that dominant steric constraints are absent.28 Seminal studies by O’Hagan and co-workers have described both fluorine-ester and fluorine-amide gauche effects,29,30 and disclosed that this conformational preference is augmented in 2-fluoroethanol and 2-fluoroethylamine when protonated.31 Studies from this laboratory have established analogous conformational behavior in β-fluoroimines,32 structurally modified N-heterocyclic carbenes,33−35 and most recently in sulfoxides and sulfones (Figure 4).36−38 However, the expansive nature of Lewis base (organo)catalysis39 has led us to intensively focus on β-fluoroamines and iminium ions as platforms to investigate noncovalent interactions. The reversible nature of various organocatalytic transformations allows topological preorganization to be achieved in a dynamic sense.

Figure 5. Fluorinated organocatalysts used for the stereoselective epoxidation of alkenes.

particularly prominently in the development of stereoselective small molecule catalysts for epoxidation, Stetter and conjugate addition processes (Figures 5 and 6). Since this subject has been comprehensively reviewed elsewhere,3−8 the following subsection is limited to selected examples in which molecular

Figure 4. Generalized fluorine gauche effect with Period 2 and 3 elements.

Figure 6. Rovis’ fluorinated NHC catalysis. 1703


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Accounts of Chemical Research editing with fluorine has had a notable effect on catalysis efficiency (vide infra).

2. C(sp3)−F CENTERS IN CYCLIC SCAFFOLDS An early example highlighting the strategic value of configurationally defined C(sp3)−F centers in governing selectivity is the epoxidation of unfunctionalized alkenes catalyzed by an αfluoroketone reported by Marples (Figure 5).40 Although no selectivities are reported in this study, it is postulated that fluorine incorporation enhances the reactivity of the transient dioxirane species that is generated in situ. This is in line with previous studies by Curci and co-workers for the related CF3 system.41 Conversely, fluorination curbs both the reactivity and selectivity of the venerable Shi catalyst toward alkene epoxidation.42 This example is nonetheless instructive since it demonstrates that a seemingly innocent H → F substitution likely disfavors the proposed spiro-transition state that underpins selectivity.42 Seminal studies by Armstrong43,44 and Denmark45,46 have validated fluorinated tropinone scaffolds as efficient catalysts for the stereoselective epoxidation of alkenes. Selectivities derive from the rigid alkaloid framework in which the amine moiety inhibits alkene approach to the top face of the transient dioxirane generated upon oxidation. α-Halogenated ketones also feature in Solladié-Cavallo and co-worker’s enantioselective epoxidation of electron-deficient alkenes.47 Again, the presence of the axial α-fluorine substituent is crucial for reactivity, since a simple F → Cl substitution leads to a dramatic drop in catalytic efficiency. Any discussion of stereoselective epoxidation catalysts would be incomplete without highlighting the based on C2 symmetric ketones from Yang,48 Denmark,43 and Behar.49 In the context of this Account, the latter two contributions are particularly relevant since they both employ flanking C(sp3)−F moieties. Control experiments with the nonfluorinated analogs clearly demonstrate the stereoelectronic importance of the fluoro substituents on yield and enantioselectivity. In the arena of NHC catalysis, configurationally defined ring fluorination played a pivotal role in Rovis’ Stetter catalyst design (Figure 6).50 The enhanced reactivity and selectivity of the fluorinated versus the nonfluorinated system is attributable to a change in the conformation of the pyrrolidine ring switching from the Cγendo conformation (in the case of H) to a Cγ-exo (in the case of fluorine).51 A computational interrogation of the catalytic cycle by Houk and co-workers revealed that the pyrrolidine ring exclusively adopts the exo conformation regardless of the catalyst used (H or F) in the acyl anion formation step.52 This powerful catalyst platform has also been employed in the annulation of enals to form 3,4-disubstituted cyclopentanones.53 Finally, extension to the dearomatization of pyridine to dihydropyridine substituted in the 4 position underscores the versatility of this catalyst system.54 The importance of ring fluorination, and indeed the configuration of the fluorine center, features prominently in List and Chandlers’ enantioselective transannular aldolization of cyclic diketones (Figure 7, top).55 Exploiting trans-4-fluoro proline for enamine catalysis, the authors incorporate this transformation in a concise synthesis of the natural product (+)-hirsutene. Importantly, trans-4-fluoro proline outperforms cis-4-fluoro proline (75% conversion, er 90:10 versus 50% conversion, er 79:21). Since fluorine is embedded in a βfluoroamine motif, we postulate that a gauche effect in the transsystem optimizes the ring conformation in the enantiodetermining step.3 A similar gauche effect analysis is instructive in

Figure 7. Examples of fluorinated pyrrolidine derivatives for enantioselective enamine catalysis.

rationalizing the highly diastereoselective alkylation of 4-fluoro proline methyl esters.56 Augmenting ring conformation toward the Cγ-endo conformation by fluorine introduction also features in a study by Alexakis and co-workers (Figure 7, bottom).57 In the context of enamine catalysis, the alkylation of aldehydes with vinyl sulfones was explored giving high yields and enantioselectivities. Importantly, the authors note that fluorination augments efficiency and while OBn → F exchange preserved the selectivity (both substituents favor a Cγ-endo conformation)58 the yields are dramatically decreased.

3. C(sp3)−F CENTERS IN ACYCLIC SCAFFOLDS In contrast to cyclic conformational control, the strategic utilization of fluorine effects to control conformation in acyclic systems is comparatively underdeveloped. However, an insightful example from Yang and co-workers demonstrates the versatile nature of the strategy. The authors reported that a β-fluoroamine derived from diphenylprolinol is a highly competent catalyst for the epoxidation of various alkenes (Figure 8). Indeed, enantioselectivities of up to 50% were

Figure 8. Yang’s epoxidation of alkenes catalyzed by a β-fluoroamine.

recorded and the authors tentatively postulate the importance of stabilizing charge-dipole effects in preorganizing the protonated catalyst.59 Cumulatively, these examples constitute a persuasive argument for a more detailed, systematic analysis of fluorine stereoelectronic effects in molecular design. Efforts from this laboratory to formulate general guidelines to achieve topological preorganization harnessing fluorine stereoelectronic effects in acyclic systems are discussed in the following section. 1704


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4. FLUORINE STEREOELECTRONIC CONTROL IN IMINIUM ION ORGANOCATALYSIS: ACYCLIC CONFORMATIONAL CONTROL Catalysis efficiency in Nature is a manifestation of structural preorganization via the interplay of stabilizing noncovalent interactions. Rate acceleration and selectivity are a consequence of precision and synergy in the spacial arrangement of substrate and catalyst.60 Biological catalysts have evolved to exploit stabilizing phenomena to provide structure and orchestrate reactivity.61 This is in sharp contrast with acyclic conformational control (ACC) in a laboratory paradigm where conformation is often a consequence of avoiding destabilizing interactions. The veritable toolbox available to synthetic chemists includes 1,2- and 1,3-allylic strain and syn-pentane interactions among others.62−64 Struck by this variance, we sought to endorse a concept antipodal to steric control to emulate biocatalysts, and simultaneously access defined conformer populations that are inaccessible by classic acyclic conformational control. Strategic incorporation of fluorine into organic scaffolds of interest offers the possibility to reconcile this difference and begin to take advantage of the stability and low-lying σ* orbital of the C(sp3)−F bond. The donor− acceptor model exemplified by the fluorine gauche effect as delineated in the introduction was a logical starting point.

a general gauche effect and a secondary interaction to populate one of two closely similar conformers is a pervasive theme in our small molecule catalysis program. Specifically, it was envisaged that iminium ions derived from (S)-2-(fluorodiphenylmethyl)-pyrrolidine66 and simple α,βunsaturated aldehydes would be highly preorganized on account of reinforcing hyperconjugative (σC−H → σC−F*), electrostatic (N+···Fδ−), and π-stacking interactions to favor the syn-clinal endo conformer depicted in Figure 9. While C−N+ and Cδ+−Fδ− dipole minimization would have tipped the torsional balance toward the synclinal exo conformation (vide infra), the presence of the phenyl groups favors the synclinalendo arrangement. It was reasoned that this fluorine-iminium ion gauche effect67 would thus position the phenyl groups on the fluorine−bearing carbon in a highly predictable area of chemical space.68 Consequently, an incoming nucleophile would be directed to the lower Si face of the transient Eiminium chain.69 To validate this reversible conformational strategy to facilitate enantioinduction in a catalysis setting, the epoxidation of enals using hydrogen peroxide70 was explored (Figure 10). The commercial catalyst71 (10 mol % loading) was employed in CHCl3 as reaction medium at ambient temperature with hydrogen peroxide as the oxidant. Gratifyingly, the enantioselective epoxidation of transcinnamaldehyde proved to be highly efficient (96% ee).72 The importance of the fluorine was demonstrated by a simple deletion experiment which resulted in a loss of enantioselectivity (84% ee). This effect was also evident from the control experiments in which the phenyl shielding groups were

The Fluorine-Iminium Ion Gauche Effect

Replacing a fluorine atom at one end of the 1,2-difluoroethane axle with a sterically noncompromising electron withdrawing group preserves the dihedral angle that one intuitively expects from stereoelectronic theory. Moreover, when introducing substituents to either carbon atom of the C(sp3)−C(sp3) core, the possibility of generating a torsional balance presents itself (gauche1 versus gauche2, Figure 9 top). This allows the conformation to be refined by the strategic introduction of stabilizing noncovalent interactions such π-stacking or cation-π interactions65 to generate highly preorganized intermediates as depicted in Figure 9 (bottom). Exploiting the synergy between

Figure 9. Evolution of the fluorine-iminium ion gauche effect. Gauche1 refers to the synclinal-exo conformation, and gauche2 refers to the synclinal-endo conformation.

Figure 10. Enantioselective, organocatalytic epoxidation of enals facilitated by the fluorine-iminium ion gauche effect. 1705


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Accounts of Chemical Research removed. Whereas 16% ee was recorded for the methyl derivative, switching to the fluoromethyl unit furnished the product in 25% ee. Interestingly, X-ray analysis of the iminium salt derived from the monofluoromethyl catalyst revealed a synclinal-exo conformation which minimizes the C−N+ and Cδ+−Fδ− dipoles (cf. synclinal-endo in the parent system). Finally, the trityl derivative was explored for comparison and gave similar levels of enantioselectivity but with a reduction in yield. The substrate scope of this transformation proved to be broad with a range of aromatic (up to 96% ee) and aliphatic enals (up to 95% ee) being smoothly processed to the corresponding epoxides. Cyclic enals were also excellent substrates for this transformation (up to 98% ee for the 15membered ring). To expand the fluorine-iminium ion gauche effect to related transformations in organocatalysis, the enantioselective aziridination of cyclic enals73 using N-Boc-O-tosylhydroxylamine as the “nitrene” source was investigated (Figure 11).74,75

Figure 12. Generating conformational equivalents by synergistic use of the fluorine gauche effect and a second noncovalent interaction. Gauche1 refers to the synclinal-exo conformation, and gauche2 refers to the synclinal-endo conformation.

with the pendant iminium chain.80−82 Indeed, a “windshield wiper” model has been invoked to describe this dynamic conformational behavior by Seebach, Grimme, and co-workers.83 Indeed, structural analyses by this laboratory have established a correlation between the quadrupole moment of the aryl shielding group and the enantioselectivity in model transformations indicating that the conformation of the iminium salts is a manifestation of a cation-π interaction.84,85 To interrogate the CH−π and π−π conformers (Figure 12, bottom), it was reasoned that the introduction of a configurationally defined fluorine atom at the benzylic position of the catalyst core would allow the equilibrium to be biased. It was envisaged that synergy between the configuration of the fluorine center and either a CH−π or π−π interaction would encode specifically for gauche1 or gauche2. Since these diastereomeric, fluorinated systems mimic the dynamic equilibrium operational in Seebach and Grimme’s windshield wiper model, they are termed “conformer equivalents” and have been instructive in understanding the origin of selectivity in Friedel−Crafts and conjugate addition reactions. Simplifying the conformational dynamics of common cinchona alkaloid-based quaternary ammonium salts has also been achieved by strategically embedding a β-fluoroammonium moiety in a catalyst of interest (Figure 13). In the natural

Figure 11. Enantioselective, organocatalytic aziridination of enals facilitated by the fluorine-iminium ion gauche effect.

Reactions were performed in n-heptane with NaOAc as the base and 20 mol % catalyst loading at ambient temperature. A library of bicyclic aziridines was generated (up to 98% ee). These materials can be rapidly converted to unnatural amino acids by simple functional group manipulations and adjustment of the carbonyl oxidation state. Having explored the synthetic utility of the fluorine-iminium ion gauche effect in catalysis, a concept that has since been exploited in other programs,76,77 the capacity to bias this torsional balance provided an opportunity to interrogate the iminium ions derived from MacMillan’s venerable first generation catalyst (Figure 12, top).78 Upon unification with an α,β-unsaturated aldehyde, the intermediate iminium salt has noteworthy on account of the three sp2-centers embedded in the 5-membered ring, together with a gem-dimethyl unit. This generates a planar core that allows the flanking benzyl group to engage in stabilizing CH−π interactions with the syn-methyl group [N+CH2CH2−Hδ+···Ph],79 or to form π−π-interactions 1706


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Figure 14. Catalytic, vicinal difluorination of alkenes.

degree of complementarity in the catalysis conditions and substrate scope provide a broad solution to what was a conspicuous absence in the catalysis ordinance.96

5. CONCLUSIONS That organic synthesis naturally gravitates toward the interrogation of function and properties is intuitive. Elegantly articulated by Eschenmoser,1 designing customized materials with tailored properties is likely to preoccupy natural scientists for the foreseeable future. Organofluorine chemistry has much to offer in this regard. The dearth of naturally abundant organic fluorine-containing compounds is suggestive of the potential chemical space yet to be explored.

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Figure 13. Exploiting a fluorine-ammonium ion gauche effect in the enantioselective fluorination of β-ketoesters.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

alkaloids, internal rotations around the C8−C9 and C9−C4′ bonds gives rise to four low energy conformers.86,87 However, exploiting hyperconjugative (σCH → σCF*) and electrostatic interactions (N+···Fδ−), the gauche effect in the quaternary ammonium salt simplifies the conformational behavior. Application in the catalytic fluorination of β-ketoesters revealed that the fluorinated catalysts were highly competent (up to 82% ee). Intriguingly, substituting F by H, OMe, OH, or OTMS had a detrimental effect on the enantioselectivity. Detailed NMR analyses allowed a tentative induction model to be formulated, indicating that the fluorine gauche effect is instrumental in preorganizing the catalyst-enolate complex prior to fluorination with NFSI.88 This conformational control strategy has also been employed in the design of novel surface modifiers for the enantioselective, heterogeneous hydrogenation of activated ketones.89,90 The strategic introduction of the F−C−C−X moiety in systems of interest allows the conformation to be predictably controlled. Given the power of Lewis base catalysis in contemporary synthesis, it is perhaps unsurprising that X = N in most cases. Installation of the parent 1,2-difluoroethylene motif (X = F) is synthetically challenging, and so as part of a program directed toward enantioselective dihalogenation,91 recent efforts have been focused on devising a catalytic, vicinal difluorination of alkenes (Figure 14). Pioneering studies by Hara and Yoneda et al. demonstrated that simple alkenes could be efficiently difluorinated with stoichiometric p-iodotoluene difluoride and Et3N·5HF.92 Inspired by this seminal report, this laboratory,93 together with a contemporaneous report by Jacobsen and co-workers94 have translated this stoichiometric process to a catalytic manifold. Common to both strategies are simple aryl iodide catalysts, an oxidant and an inexpensive source of fluoride to generate the ArIF2 species in situ.95 A

ORCID

Ryan Gilmour: 0000-0002-3153-6065 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies Marialuisa Aufiero (1986) undertook her studies in chemistry at University “La Sapienza” in Rome (L. Mandolini). She obtained her Ph.D. at the ETH Zürich (F. Schoenebeck) and is currently a postdoctoral researcher at WWU Münster (R. Gilmour). Ryan Gilmour (1980) was educated at the universities of St Andrews and Cambridge. He held research fellowships at the Max-PlanckInstitut für Kohlenforschung (A. Fürstner) and the ETH Zürich (P. H. Seeberger) before being appointed as Alfred-Werner-AssistantProfessor at the ETH Zürich (2008−2012). He is currently chair of organic chemistry and chemical biology at the Westfälische WilhelmsUniversität Münster.

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ACKNOWLEDGMENTS We thank Dr. Christian Mück-Lichtenfeld for assistance in generating Figure 2.

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DEDICATION This manuscript is dedicated to Prof. Scott E. Denmark on the occasion of his 65th birthday. 1707


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