Angewandte Minireviews Chemie 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 interac- tions (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 inter- action 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. 2 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2018, 57,2–11 Ü Ü These are not the final page numbers! Angewandte Minireviews Chemie 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 encapsulat- ing 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-cyclo- pentadiene 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. Angew. Chem. Int. Ed. 2018, 57, 2 – 11 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 3 These are not the final page numbers! Ü Ü Angewandte Minireviews Chemie 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.