Fluorine in a C−F Bond As the Key to Cage Formation

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International Edition: DOI: 10.1002/anie.201710423 Fluorinated Cage Molecules German Edition: DOI: 10.1002/ange.201710423 Fluorine in a CÀF Bond as the Key to Cage Formation Maxwell Gargiulo Holl, Cody Ross Pitts, and Thomas Lectka* cage molecules · fluorine · hydrogen bonds · neighboring group effects · noncovalent interactions

Cage molecules have long been employed to trap reactive or transient species, as their rigid nature allows them to enforce situations that otherwise would not persist. In this Minireview, we discuss our use of rigid cage structures to investigate the close noncovalent interactions of fluorine with other functional groups and determine how mutual proximity affects both physical properties and reactivity. Unusual Weak cages are exemplified by inter- covalent interactions of fluorine are also explored: the cage can close actions of the CÀF bond with C=C and to form the first solution-phase C-F-C fluoronium ion. C=O bonds, stronger cages are re- vealed by hydrogen bonding interactions (F···HO, F···HC); and a B···F 1. Introduction interaction is only predicted to form a cage in its transition state. The strongest cage is represented As the most electronegative element, fluorine usually gets by a symmetrical C-F-C fluoronium ion, in which the C-F-C its way with other atoms, much in the manner a wild cat gets interaction is highly covalent. A weak cage arises again in his way with prey. Once part of a CÀF bond, the fluorine atom novel aromatic substitution chemistry in which F interacts is tamed and has a much-diminished desire to interact with an aryl ring. strongly with other species. What would it then take to get For a starting system, we turned for inspiration to the fluorine, as part of a CÀF bond, to do the chemists bidding? decahydro-1,4,5,8-dimethanonaphthalene skeleton, made in One possibility is to capture it within a cage, or else to make it substituted form by Winstein and Svensson,[2] and later in part of the structure of the cage itself. In fact, the cages of unsubstituted form by Ermer.[3] Hydrogen bonding interac- particular interest to us are not of the “encapsulating” form, tions of the one-carbon bridge substituents partly close the in which the cage totally surrounds an entrapped entity. cage, whereas a fluoronium would fully close it (Scheme 2). Instead, we have explored the “interacting” forms, in which the cages anchor substituents and set the stage for very close intramolecular contacts (both covalent and noncovalent), thus making fluorine in essence part of the cages structure. In the history of organic chemistry, this type of system has most notably permitted the characterization of some remarkably short nonbonded H···H and H···Ar interactions.[1] Our particular stratagem is to place fluorine, as part of aCÀF bond, within an “open door” cage precursor whereby it is pointed directly at, and could interact at close range with, a prominent organic functional group. The resulting interaction would thus effectively shut the “door” to the cage. Shown in Scheme 1 are several molecules, each representing a different molecular interaction between fluorine and a closely positioned functional group. The interactions, which are of various strengths, define the “tightness” of the cage.

[*] M. G. Holl, Dr. C. R. Pitts, Prof. T. Lectka Department of Chemistry, Johns Hopkins University 3400 North Charles St., Baltimore, MD 21218 (USA) E-mail: [email protected] The ORCID identification number(s) for the author(s) of this article can be found under: Scheme 1. An array of cage systems (with interactions ranging from https://doi.org/10.1002/anie.201710423. very weak to strong) we have made.

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Maxwell Gargiulo Holl obtained his B.A. from Johns Hopkins University in 2014 and is currently a Ph.D. student at Johns Hopkins with Prof. Thomas Lectka.

Scheme 2. General structure of the decahydro-1,4,5,8-dimethano-naph- thalene skeleton in both open, partly closed, and fully closed forms.

A couple of ingenious species are known for encapsulating fluoride, or a covalent XÀF linkage in a cage,[4] as Cody Ross Pitts obtained his B.S. from sometimes in olden days aforementioned wild cats were put in Monmouth University in 2010, completing his honors thesis research under Prof. Massi- cages for good or ill. For instance, Bassindale and co-workers miliano Lamberto. He joined the group of have synthesized an inclusion compound in which a lone Prof. Thomas Lectka at Johns Hopkins fluoride ion resides in a siloxane cage (1, Figure 1).[4a] University in 2011. After completion of his Additionally, Pascal and co-workers have ensconced a silyl Ph.D. research, he began pursuing postdoc- fluoride linkage in a cage that forces it into close proximity toral research with Prof. Antonio Togni at with the p-system of an arene (2, Figure 1).[4c,d] ETH Zrich in 2017.

Prof. Thomas Lectka graduated with a B.A. in Chemistry from Oberlin College in 1985. He then pursued his Ph.D. at Cornell with Prof. John McMurry, finishing in 1990. He undertook postdoctoral studies as an Alexander von Humboldt Fellow at Heidel- berg in 1991 with Rolf Gleiter, followed by an NIH Fellowship at Harvard University with Prof. David Evans. He joined the Johns Hopkins chemistry faculty in 1994, where he is now Jean and Norman Scowe Profes- Figure 1. Known compounds with caged fluorine atoms. sor of Chemistry.

From a more general standpoint, cage molecules are venerable in the history of non-natural products chemistry, ophile 5 is the highly fortuitous cis-disposition of the CÀF wherein they serve as architecturally intricate scaffolds for bond and the unsaturated anhydride ring. The remarkable remarkable cations, radicals, and other reactive intermediates selectivity of this Diels–Alder reaction (only traces of the not easily accessible by other means. They can be small, like trans isomer are observed) has been ascribed to the con- cubane,[5] in which nothing can fit, or they can be large like the troversial “Cieplak effect”.[11] fullerenes[6] or the amazing supramolecular structures that Reaction of 5 with 1,3-cyclopentadiene affords two abound in todays literature and that can accommodate guests diastereomers 6 and 7 in roughly equal quantities with ease.[7] From an aesthetic point of view, cage molecules (Scheme 3).[12] Isomer 6 shows the F atom jammed against are often architecturally elegant,[8] and have engendered an H atom on the opposite bridge. The through-space colorful trivial names in the chemical lexicon, as so eloquently coupling constant (JHF = 7.4 Hz) is indicative of a fairly tight recounted in Nickons and Silversmiths “The Name Game.”[9]

2. First Forays: Interaction of CÀF Bonds with CÀH and C=C Bonds

The construction of cage molecules often utilizes the Diels–Alder reaction; thus we anticipated that a series of Diels–Alder reactions could lead to the basic open-cage framework. Our endeavor started with 5-fluoro-1,3-cyclopentadiene 3 generated in situ; this species can be trapped with dimethylacetylene dicarboxylate 4.[10] Hydrogenation and anhydride formation result in the key dienophile 5 which plays a prominent role in much of the chemistry highlighted Scheme 3. Synthesis of dienophile 5 and first probe molecules 6 and within this Minireview. The most notable feature of dien- 7.

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interaction between them. Likewise, isomer 7 shows a close interaction of the F atom, this time with the C=C bond constituting the opposing bridge. In both cases, a bond critical point (BCP), in atoms-in-molecules (AIM) parlance, exists between F and the opposing H atom or C=C bond. Espe- cially in the latter case, it is debatable whether this interaction is strong enough to consider it as a formal cage (in fact it may be repulsive), never- theless, spin–spin couplings between 19F, 13C, and the vinyl 1H atoms reveal significant perturbations. The radical cation of 7 (7+) presumably formed in the corresponding EI mass spectrum, reveals a much stronger interaction (d(C···F) = 2.40 at wB97xd/6-311 + g**; same used for all calculations except 8-I) as opposed to 2.68 in 7, and a BCP higher in magnitude. In any event, these results serve as a warm-up for more interesting studies. Scheme 4. Synthesis of “jousting” probe compounds. DAST= (diethylamino)sulfur trifluoride, We then moved forward to synthe- Tf = trifluoromethanesulfonyl. size a series of molecules in which very close CÀF···HÀC s-bond interactions (that we nicknamed “jousting”) can be enhanced through ration of diastereomer 10 through Fleming–Tamao oxidation, both red- and blue-shifted hydrogen bonding (Figure 2).[13] triflate formation, and functional group interconversion led to These interactions were induced by the placement of various a series of products with different substituents geminal to the functional groups geminal to the HÀC bond, thereby probing inward hydrogen. the relationship between hydrogen bond strength and bond Depending on the nature of the functional group, both vibration frequencies. “Jousting” interactions appear to be an red- and blue-shifted hydrogen bonding can be induced admixture of F···H hydrogen bonding and CÀH bond relative to the standard methylene group. For example, iodide compression. The associated electronic effects resulting from 8-I produces a blue shift between F and H (d = 1.85 ), changes induced by the functional group at the X position on whereas cyanide 8-CN produces a red shift and behaves more

these systems are documented by IR, X-ray crystallography, as a classical H-bond (d(F···H) = 1.83 ); in both cases JHF is 1H NMR, and 19F NMR spectroscopy. large (38 Hz for 8-I, 50 Hz for 8-CN). As we stated, “the The synthesis of the jousting molecules (Scheme 4) is direction of the IR shift of the XÀH (in our case, CÀH stretch) more adventurous than the synthesis of the first probe is often independent of the magnitude of the interaction. In molecules. In the present case, the crucial Diels–Alder our case, the size of the through-space HÀF spin–spin reaction had to be performed under high pressure. Elabo- couplings may be more indicative of the strength of the interactions” (Scheme 5).

3. A Symmetrical Fluoronium Ion in Solution: Shutting the Door on the Cage

The interactions highlighted in the previous examples are best described as noncovalent, which means that the “door” to the cage is partly open or else weak. One way to close it completely (to form a desadamantyl type structure with a predicted CÀF distance of 1.58 ) would be through the displacement of a good leaving group by a CÀF bond at the opposing bridgehead (Scheme 6). It is no accident that a symmetrical C-F-C fluoronium ion in solution was not observed until recently—we are asking fluorine to assume Figure 2. A series of molecules with different groups geminal to the a formal positive charge in valence bond terms, or to become inward hydrogen used to probe “jousting” interactions.

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Scheme 5. Examples of blue-shifted and red-shifted F···H interactions.

Scheme 6. A C-F-C fluoronium ion and its precursor. much more positively charged (although still somewhat negative) in modern theoretical, electron-counting terms. The first experiment that we performed was the hydrolysis of triflate 11; this reaction was both surprisingly fast and clean (Scheme 7).[14] It clued us in to the fact that something unusual Scheme 8. Results of the isotopic labeling study. Hydrolysis conducted was going on during the reaction, perhaps the formation of with 20% H2O in pure TFE at 608C affords 13a + 13b (96% R =H, the fluoronium itself. Still, while this experiment provided remainder is TFE ethers). promising evidence, it was far from definitive proof.

labels proximate to the developing fluoronium bond (14 and 15). Both phenomenological isotope effects for hydrolytic disappearance of the triflate, and the corresponding appear- ance of the trapped products (alcohols), comported well with theoretical calculations (Figure 3).[15]

4. No Cage, Door Shuts, Door Cracks Open Scheme 7. Results of preliminary hydrolysis of triflate 11. TFE = 2,2,2- trifluoroethanol. We also documented a type of cage interaction in a CÀF bond directed Diels–Alder reaction.[16] The process is best illustrated by the competition experiment shown in Scheme 9, An isotopic labeling study served to clarify things. One whereby dienophile 5 outcompetes its epimer 20 in a Diels– issue with studying the unlabeled compound is that as the Alder reaction with borole 19,[17] presumably by stabilizing fluoronium intermediate is symmetrical, it is not possible to the transition state through a B···F Lewis acid/Lewis base distinguish it from its alternatives. One would expect the same reaction. Diels–Alder reactions of 5 are usually more difficult result from “simple” triflate hydrolysis or an extended SN2 to achieve than those of its sans-inward-fluorine siblings, mechanism wherein water attacks from the back of the CÀF requiring higher temperatures to proceed. Calculations bond as fluorine displaces the triflate. indicated that the low energy transition state benefits from

Deuterium-labeled isomer [D2]-11 gave an almost equal the B···F interaction (2.27 , Figure 4) which is significantly proportion of labeled products upon hydrolysis, with an ever- stronger in the transition state than in the product, where it is so slight preponderance of 13a that we attribute to a steric mitigated (now 2.60 ) by the fully formed homoaromatic isotope effect (Scheme 8). This result was strongly suggestive boracyclopentene interaction. Thus, in the starting materials of a symmetrical intermediate, but did not completely rule out there is no cage, in the transition state there is a cage albeit the possibility of rapidly equilibrating classical secondary weakly locked, and in the product the cages door is cracked carbocations, with fluorine “jumping” from bridge to bridge. open! Another way to view the situation is in analogy to a yo- To determine the nature of the intermediate, other isotope yo. effects were measured, most importantly those involving

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a salient example is provided by alcohol 27,in which a strong hydrogen bond exists between F and the OH group (d(F···O) = 2.51 by crystallography).[18] Alcohol 27 is made by the epimerization of out alcohol 8-OH through an oxidation/reduction sequence (Scheme 10). The hydrogen bond in 27 is unusual in that the frequency of its OH stretch is not much different than that of its epimer, alcohol 8-OH, in a variety of solvents (Fig- ure 5). This “no shift” bond appears deceiv- ingly to be virtually absent by IR spectrosco-

py, but in fact NMR JHF coupling constants (68 Hz) indicate a very strong interaction, which is typically not the case for CÀF···HÀO hydrogen bonds.[19] This cage, closed by hydrogen bonding (d(F···HO) = 1.59 ), is a case of an admixture of blue-shifting (bond compression) and red-shifting (traditional H- Figure 3. Kinetic isotope effects with label isomers on the one-carbon bridges are consistent with the formation of a symmetrical intermediate and agree with calculated bonding) forces cancelling each other in the values. IR spectrum. This phenomenon seems to come uniquely from the interaction of fluorine and the hydroxyl group; as discussed 5. Cage Closure through Strong Hydrogen Bonding previously, interactions with fluorine and CÀH bonds in 8 produced both blue and red shifts, and the interaction A cage system provides a perfect opportunity to turn an between a hydroxyl group and an alkene resulted in a strong ordinarily weak F···H interaction into a strong one. Such red shift.[20]

Scheme 9. Competition experiment between epimeric dienophiles. Calculations show that the B···F distance is closer in the transition state than in the product, the B···F interaction acting like a yo-yo going from long to short in the transition state, and back to longer again in the final product.

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Figure 4. Energy comparison of calculated transition states leading to different possible Diels–Alder adducts.

(Figure 6) by 6.73 ppm. This deshielding decreased (by 1 ppm) when the ketone was complexed with a bulky aluminum-based Lewis acid[23] (Scheme 11, left), showing that when an oxygen lone pair is tied up by aluminum, its ability to compress the Scheme 10. Synthesis of ketone 26 and in-OH 27. PCC = pyridinium chlorochromate. CÀF bond decreases. Attempts to form complexes with a less bulky aluminum compound resulted in binding to the anhydride carbonyls (Scheme 11, right). The said chemical shift difference is accompanied by a red-shifted carbonyl stretch (70 cmÀ1) in the IR spectrum. According to results of theoretical studies, the structure with an Figure 5. Comparison of OH stretching modes (cmÀ1) between epimers 8-OH and 27, showing little difference in frequencies despite drastically different environments. unconstrained F···C distance (compared to various fixed F···C distances) maximizes the blue-shift in the C=O stretch, and minimizes the C=O bond 6. F···Ar and F···Carbonyl Interactions: Electron length. This led us to conclude that the interaction between Density and Nuclear Shielding the fluorine atom and the ketone compels the minimum energy structure to lie at the point of balance between After our early investigations of the F···alkene interaction, competing oxygen–fluorine repulsion and incipient nucleo- we decided to synthesize new compounds that would high- philic attack on the carbonyl carbon by the fluorine atom. The light different types of F···p interactions: an F···arene interaction consists of a combination of attractive and interaction[21] and an F···carbonyl interaction.[22] Ketone 26 repulsive forces, reminiscent of the strange no-shift hydrogen proves to be an excellent model system to investigate the bond in 27. F···carbonyl interaction, which turns out to be surprisingly Turning to the F···arene interaction, we start once again complex. We obtained crystallographically-derived static with the keystone dienophile 5 (shown rotated 1808 from its electron deformation density maps that are analyzed in the previous depictions for clarity in Scheme 12) to make probe context of comparison molecules (see Figure 6). It is clear that molecule 29 through a Diels–Alder reaction with anthra- there is some repulsion occurring between the oxygen and fluorine atoms, but it is not immediately obvious to what extent an attractive fluorine lone pair···C=O p* donation (d(F···C) = 2.44 by crystallography) plays a role. Compared to nonfluori- nated control molecules, the C=O stretching frequency is blue-shifted by 20 cmÀ1,[22] which suggests that there is some steric compression between the ketone and fluorine, a fact corroborated by the relative deshield- Scheme 11. Complexes of ketone 26 with a bulky aluminum-based Lewis acid. The complex ing of 26 compared to control 28 depicted on the left red-shifts the C = O stretch by 70 cmÀ1.

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to explain this result was that deshielding from orbital compression[26] may be outcompeting ring current shielding. As the electron cloud about the fluorine atom would be distorted anisotropically by electron repulsion from the arene p-cloud that is compressing the CÀF bond, we expected to see the 13C-19F coupling constant increase.[27] This is what we found: this geminal coupling constant is greater in 29 by 21 Hz (relative to that in 33). We strove to observe directly the electronic environ- ment created by the F···arene and F···ketone interactions, so we collected X-ray data at subatomic resolution and used multiple refinements to generate static electron deformation density maps for 26 and 29, with 28[21,28] as a control compound (Figure 6). Both 26 and 29 show distortions about the fluorine compared to control 28, but in the case of ketone 26, they are much more dramatic: the symmetrical toroidal region of electron density in 28 is significantly distorted in 26. In the case of 29, the distortion is lessened, but it is evident that Scheme 12. Synthesis of 29, 32, and 33. a compressive effect is tilting the electronic structure away from the C > C- > F line.

cene.[21,24] In the resulting adduct, the fluorine atom is 7. The F···Ar Interaction: Partly Closing the Cage to positioned over the p-cloud of an aromatic ring, close to the Promote Aromatic Substitution center (d = 2.68 by crystallography to the nearest aryl carbon atom). Though fluorine as part of a CÀF bond is The prior studies on symmetrical fluoronium ions prompt- traditionally believed to not be very susceptible to anisotropic ed us to wonder whether we could use a “fluoronium-like” perturbations,[25] we thought that the proximate arene might interaction to stabilize a transition state or reactive inter- have an interesting effect on the fluorine nucleus in the NMR mediate in aromatic substitution chemistry. In a way, it would spectrum. be a different form of arene activation, with fluorines lone Whereas ring current effects traditionally effect shielding pair stabilizing positive charge on the aryl ring (Scheme 13). normal to the plane of the aromatic ring, we found that the As predicted, nitration of 29 afforded exclusive substitution fluorine nucleus of 29 is deshielded relative to its out on the top ring (Scheme 13). Control experiments indicated counterpart 33 by 15.8 ppm. The hypothesis that we devised strongly that the fluorine atom acts as a stabilizing force in the successful reaction chemistry. Using valence bond arguments, the notable “fluoronium” resonance form shows how the cage is “closed” (albeit weakly) in the intermediate and transition state (Scheme 14). Although by no means a full-fledged fluoronium ion, the principle of s-stabilization through fluorines lone pairs still ap- plies, and in this case is able to influence reaction chemistry in an unexpected way. The same fundamen- tal phenomenon was also recently utilized to direct arene functionaliza- tion diastereoselectively using per- turbing carbonyl groups.[29] It may also be possible that perturbation by the fluorine atom raises the ground state energy of the ring, which results in a lower barrier of activation.

Figure 6. Static electron deformation density map of 29, 26, and 28. Violet regions represent regions electron-rich relative to aspherical pseudoatoms, while green regions represent “electron holes.”.

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Scheme 13. Nitration of 29 and control molecules. Compound 29 nitrates exclusively on the top ring, while 32 and 33 form mixtures of adducts on both rings. TFAA =trifluoroacetic anhydride.

Acknowledgements

T.L. thanks the NSF (CHE 1465131) for support.

Conflict of interest

The authors declare no conflict of interest.

Scheme 14. The nitroarenium ion and its “fluoronium” resonance form.

8. Conclusion

The incorporation of fluorine into the body of a cage structure enabled us to probe novel noncovalent and covalent interactions of fluorine, learning about new ways in which its reactivity can be influenced by subtle forces. We also envisage some crea- tive future directions for cage interactions. Building on the H-bonding principle, a charged bond of F to NH+ and OH+ can be imagined. A stronger interaction of B and F is possible by reduction of the homoaromatic double bond mentioned in Section 5; furthermore bridging N-F-C and C-F-Si species; finally incipient attack of F as a nucleophile at an oxenium carbon atom (Figure 7). Figure 7. Potential future studies using the cage scaffold.

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[13] M. D. Struble, J. Strull, K. Patel, M. A. Siegler, T. Lectka, J. Org. [1] a) R. A. Pascal, Jr., C. G. Winans, D. Van Engen, J. Am. Chem. Chem. 2014, 79,1. Soc. 1989, 111, 3007; b) R. A. Pascal, Jr., Eur. J. Org. Chem. [14] M. D. Struble, M. T. Scerba, M. Siegler, T. Lectka, Science 2013, 2004, 3763; c) O. Ermer, S. A. Madison, F. A. L. Anet, S. S. 340, 57. Miura, J. Am. Chem. Soc. 1985, 107, 2330; d) J. Zong, J. T. [15] M. D. Struble, M. G. Holl, M. T. Scerba, M. A. Siegler, T. Lectka, Mague, R. A. Pascal, Jr., J. Am. Chem. Soc. 2013, 135, 13235. J. Am. Chem. Soc. 2015, 137, 11476. [2] T. Svensson, S. Winstein, J. Am. Chem. Soc. 1972, 94, 2336. [16] M. D. Struble, L. Guan, M. A. Siegler, T. Lectka, J. Org. Chem. [3] O. Ermer, Angew. Chem. Int. Ed. Engl. 1977, 16, 798; Angew. 2016, 81, 8087. Chem. 1977, 89, 833. [17] a) P. J. Fagan, W. A. Nugent, J. C. Calabrese, J. Am. Chem. Soc. [4] a) A. R. Bassindale, M. Pourny, P. G. Taylor, M. B. Hursthouse, 1994, 116, 1880; b) P. J. Fagan, E. G. Burns, J. C. Calabrese, J. M. E. Light, Angew. Chem. Int. Ed. 2003, 42, 3488; Angew. Am. Chem. Soc. 1988, 110, 2979. Chem. 2003, 115, 3612; b) S. E. Anderson, D. J. Bodzin, T. S. [18] M. D. Struble, C. Kelly, M. A. Siegler, T. Lectka, Angew. Chem. Haddad, J. A. Boatz, J. M. Mabry, C. Mitchell, M. T. Bowers, Int. Ed. 2014, 53, 8924; Angew. Chem. 2014, 126, 9070. Chem. Mater. 2008, 20, 4299; c) S. Dell, N. J. Volegaar, D. M. Ho, [19] a) G. T. Giuffredi, V. Gouverneur, B. Bernet, Angew. Chem. Int. R. A. Pascal, Jr., J. Am. Chem. Soc. 1998, 120, 6421; d) S. Dell, Ed. 2013, 52, 10524; Angew. Chem. 2013, 125, 10718; b) H.-J. D. M. Ho, R. A. Pascal, Jr., J. Org. Chem. 1999, 64, 5626; e) V. Schneider, Chem. Sci. 2012, 3, 1381; c) J. D. Dunitz, R. Taylor, Amednola, M. Boiocchi, L. Fabbrizzi, N. Fusco, Eur. J. Org. Chem. Eur. J. 1997, 3, 89. Chem. 2011, 6434. [20] M. D. Struble, M. G. Holl, G. Coombs, M. A. Siegler, T. Lectka, [5] P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157. J. Org. Chem. 2015, 80, 4803. [6] H. W. Kroto, A. W. Allaf, S. P. Balm, Chem. Rev. 1991, 91, 1213. [21] M. G. Holl, M. D. Struble, P. Singal, M. A. Siegler, T. Lectka, [7] J.-M. Lehn, Science 1985, 227, 849. Angew. Chem. Int. Ed. 2016, 55, 8266; Angew. Chem. 2016, 128, [8] a) W. Fessner, G Sedelmeier, P. R. Spurr, G. Rihs, H. Prinzbach, 8406. J. Am. Chem. Soc. 1987, 109, 4626; b) U. Biethan, U. V. Gizycki, [22] M. G. Holl, M. D. Struble, M. A. Siegler, T. Lectka, J. Fluorine H. Musso, Tetrahedron Lett. 1965, 6, 1477; c) M. Rey-Carrizo, M. Chem. 2016, 188, 126. Barniol-Xicota, M. Font-Bardia, S. Vzquez, Angew. Chem. Int. [23] S. Saito, H. Yamamoto, Chem. Commun. 1997, 1585. Ed. 2014, 53, 8195; Angew. Chem. 2014, 126, 8334; d) H. [24] a) M. Avram, I. G. Dinulescu, C. D. Nenitzescu, Justus Liebigs Prinzbach, K. Weidmann, S. Trah, K. Knothe, Tetrahedron Lett. Ann. Chem. 1966, 691, 9; b) S. E. Wheeler, A. J. McNeil, P. 1981, 22, 2541; e) L. A. Paquette, R. J. Ternansky, D. W. Balogh, Muller, T. M. Swager, K. N. Houk, J. Am. Chem. Soc. 2010, 132, G. Kentgen, J. Am. Chem. Soc. 1983, 105, 5446; f) W.-D. Fessner, 3304. B. A. R. C. Murty, J. Worth, D. Hunkler, H. Fritz, H. Prinzbach, [25] W. R. Dolbier, Jr., Guide to Fluorine NMR for Organic Chem- W. D. Roth, P. v. R. Schleyer, A. B. McEwen, W. F. Maier, ists, Wiley, Hoboken, 2009, p. 11. Angew. Chem. Int. Ed. Engl. 1987, 26, 452; Angew. Chem. [26] E. Kleinpeter, S. Klod, J. Am. Chem. Soc. 2004, 126, 2231. 1987, 99, 484. [27] a) I. Nowak, J. Fluorine Chem. 1999, 99, 59; b) T. Takemura, T. [9] A. Nickon, E. F. Silversmith, Organic Chemistry: The Name Sato, Can. J. Chem. 1976, 54, 3412. Game: Modern Coined Terms and Their Origins, Permagon, [28] K. Kanno, M. Kira, Chem. Lett. 1999, 28, 1127. New York, 1987. [29] K. E. Murphy, J. L. Bocanegra, X. Liu, H.-Y. K. Chau, P. C. Lee, [10] M. A. McClinton, V. Sik, J. Chem. Soc. Perkin Trans. 1 1992, J. Li, S. T. Schneebeli, Nat. Commun. 2017, 19, 9181. 1891. [11] a) J. M. Coxon, D. Q. McDonald, Tetrahedron Lett. 1992, 33, 651; b) J. B. Macaulay, A. G. Fallis, J. Am. Chem. Soc. 1990, 112, 1136. Manuscript received: October 9, 2017 [12] M. T. Scerba, S. Bloom, N. Haselton, M. Siegler, J. Jaffe, T. Accepted manuscript online: November 15, 2017 Lectka, J. Org. Chem. 2012, 77, 1605. Version of record online: && &&, &&&&

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Fluorinated Cage Molecules An open and shut case with fluorine: Rigid cage structures can be used to M. G. Holl, C. R. Pitts, investigate the close noncovalent inter- T. Lectka* &&&& — &&&& actions of fluorine with other functional groups and to determine how mutual Fluorine in a CÀF Bond as the Key to Cage proximity affects both physical properties Formation and reactivity. An unusual covalent interaction of fluorine leads to closure of the cage, resulting in the first solution-phase C-F-C fluoronium ion.

Angew. Chem. Int. Ed. 2018, 57, 2 – 11 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 11 These are not the final page numbers! Ü Ü