Can the -CF3 Group Act as a Tight, Well-Defined Hydrogen Bond Acceptor? A Clear Crystallographic CF2-F···H-N+ Interaction Says Yes.

The CF3 group is well noted for being noninteractive with other functional groups. In this Note, we present a highly rigid model system containing a significant hydrogen bonding interaction between a charged N-H donor and a CF3 acceptor that challenges this accepted wisdom. Spectroscopic and single crystal X-ray crystallography data characterize this interaction, consistent with a weak to moderate hydrogen bond that would be difficult to observe in an intermolecular system.

Metal Ion-Induced Large Fragment Deactivation: A Different Strategy for Site-Selectivity in a Complex Molecule.

Complex natural product functionalizations generally involve the use of highly engineered reagents, catalysts, or enzymes to react exclusively at a desired site through lowering of a select transition state energy. In this communication, we report a new, complementary strategy in which all transition states representing undesirable sites in a complex ionophore substrate are simultaneously energetically increased through the chelation of a metal ion to the large fragment we wish to neutralize. In the case of an electrophilic, radical based fluorination reaction, charge repulsion (electric field effects), induced steric effects, and electron withdrawal provide the necessary deactivation and proof of principle to afford a highly desirable natural product derivative. We envisage that many other electrophilic or charge based synthetic methods may be amenable to this approach as well.

Competition between C-C and C-H Bond Fluorination: A Continuum of Electron Transfer and Hydrogen Atom Transfer Mechanisms.

In 2015, we reported a photochemical method for directed C-C bond cleavage/radical fluorination of relatively unstrained cyclic acetals using Selectfluor and catalytic 9-fluorenone. Herein, we provide a detailed mechanistic study of this reaction, during which it was discovered that the key electron transfer step proceeds through substrate oxidation from a Selectfluor-derived N-centered radical intermediate (rather than through initially suspected photoinduced electron transfer). This finding led to proof of concept for two new methodologies, demonstrating that unstrained C-C bond fluorination can also be achieved under chemical and electrochemical conditions. Moreover, as C-C and C-H bond fluorination reactions are both theoretically possible on 2-aryl-cycloalkanone acetals and would involve the same reactive intermediate, we studied the competition between single-electron transfer (SET) and apparent hydrogen-atom transfer (HAT) pathways in acetal fluorination reactions using density functional theory. Finally, these analyses were applied more broadly to other classes of C-H and C-C bond fluorination reactions developed over the past decade, addressing the feasibility of SET processes masquerading as HAT in C-H fluorination literature.

Through-Space, Lone-Pair Promoted Aromatic Substitution: A Relay Mechanism Can Beat Out Direct Activation.

We report a detailed experimental and theoretical analysis of through-space arene activation with halogens, tetrazoles and achiral esters and amides. Contrary to previously assumed direct activation through σ-complex stabilization, our results suggest that these reactions proceed by a relay mechanism wherein the lone pair-containing activators form exothermic π-complexes with electrophilic nitronium ion before transferring it to the probe ring through low barrier transition states. Noncovalent interactions (NCI) plots and Quantum Theory of Atoms in Molecules (QTAIM) analyses depict favorable interactions between the Lewis base (LB) and the nitronium ion in the precomplexes and the transition states, suggesting directing group participation throughout the mechanism. The regioselectivity of substitution also comports with a relay mechanism. In all, these data pave the way for an alternate platform of electrophilic aromatic substitution (EAS) reactions.

An Electrochemical Approach to Directed Fluorination.

Electrosynthesis has made a revival in the field of organic chemistry and, in particular, radical-mediated reactions. Herein, we report a simple directed, electrochemical C-H fluorination method. Employing a dabconium mediator, commercially available Selectfluor, and RVC electrodes, we provide a range of steroid-based substrates with competent regioselective directing groups, including enones, ketones, and hydroxy groups, as well as never reported before lactams, imides, lactones, and esters.

C-C Bond Activation and Demethylenation of Epoxides by Amine Radical Dications.

In this note, we explore a unique reactivity pattern that involves a rare radical-based C-C bond scission of epoxides followed by demethylenation. The reaction is accomplished by Selecfluor and its radical dication working in tandem; a mechanism supported by experiment and DFT calculations is proposed that involves the generation and identification of a key reactive intermediate. The reaction seems to be fairly general for 1,1-disubstituted epoxides.

Photoactivated Pyridine Directed Fluorination through Hydrogen Atom Transfer.

We have established hydrogen atom transfer (HAT) as the key player in a directed, photopromoted fluorination of pyridylic groups. The Lewis basic pyridyl nitrogen directs amine radical dication propagated HAT and Selectfluor fluorination of various ortho substituents in a highly regioselective manner with little to no side product formation. A variety of pyridines and quinolines were employed to showcase the directing capability of the nitrogen atom. Additionally, both experimental and computational data are provided that illuminate how this mechanism differs from and complements prior work in the area.

Spectroscopic and Crystallographic Characterization of the R3 N+ -C-H⋠⋠⋠X Interaction.

As appreciation for nonclassical hydrogen bonds has progressively increased, so have efforts to characterize these interesting interactions. Whereas several kinds of C-H hydrogen bonds have been well-studied, much less is known about the R3 N+ -C-H⋅⋅⋅X variety. Herein, we present crystallographic and spectroscopic evidence for the existence of these interactions, with special relevance to Selectfluor chemistry. Of particular note is the propensity for Lewis bases to engage in nonclassical hydrogen bonding over halogen bonding with the electrophilic F atom of Selectfluor. Further, the first examples of 1 H NMR experiments detailing R3 N+ -C-H⋅⋅⋅X (X=O, N) hydrogen bonds are described.

Rational Computational Design of Systems Exhibiting Strong Halogen Bonding Involving Fluorine in Bicyclic Diamine Derivatives.

Perhaps the most controversial and rare aspect of the halogen bonding interaction is the potential of fluorine in compounds to serve as a halogen bond donor. In this note, we provide clear and convincing examples of hypothetical molecules in which fluorine is strongly halogen bonding in a metastable state. Of particular note is a polycyclic system inspired by Selectfluor, which has been controversially proposed to engage in halogen bonding.

C-F Bonds as "Frozen" Nucleophiles: Unconsummated SN2 Reactions.

In this note, we present a series of rigid molecules that show close enforced interactions between Ar-F moieties and -CH2X groups in a "tetrel bond" configuration similar to a nascent SN2 attack. We explore the spectroscopic, crystallographic, and chemical reactivity consequences of these unusual interactions, including significant through-space spin-spin couplings, short C-F···CH2X distances, and differential SN1 and SN2 reaction pathways. We also reveal experimental evidence of carbon-based tetrel bonds influencing chemical reactivity in solution. Finally, density functional theory (DFT) calculations are employed throughout this study to confirm and illuminate our experimental data.

The Close Interaction of a C-F Bond with an Amide Carbonyl: Crystallographic and Spectroscopic Characterization.

The putative interaction of a C-F bond with an amide carbonyl has been an intriguing topic of interest in this century for reasons spanning basic physical organic chemistry to biochemistry. However, to date, there exist no examples of a close, well-defined interaction in which its unique aspects can be identified and exploited. Herein, we finally present an engineered system possessing an exceptionally tight C-F-amide interaction, allowing us to obtain spectroscopic, crystallographic, and kinetic details of a distinctive, biochemically relevant chemical system for the first time. In turn, we also explore Lewis acid coordination, C-F bond promotion of amide isomerization, enantiomerization, and ion protonation processes.

Quest for a Symmetric [C-F-C]+ Fluoronium Ion in Solution: A Winding Path to Ultimate Success.

In this Account, we chronicle our tortuous but ultimately fruitful quest to synthesize a [C-F-C]+ fluoronium ion in solution, thus providing the last piece of the organic halonium ion puzzle. Inspiration for the project can be traced all the way back to the graduate career of the corresponding author, wherein the analogy between a [C-H-C]+ "hydrido" bridge and a hypothetical [C-F-C]+ bridge was first noted. The earliest attempt to construct a bicyclo[5.3.3]tridecane-based fluoronium ion (based on the analogous hydrido bridged cation) proved to be synthetically difficult. A subsequent attempt involving a 1,8-substituted naphthalene ring was theoretically naïve in retrospect, and it resulted in a classical benzylic carbocation instead. A biphenyl-based substrate, although computationally sound, proved to be kinetically untenable. At last, after some tweaking (including a dead-end detour into a fluoraadamantane skeleton), we finally achieved success with a highly rigid, semicage precursor based on the decahydro-1,4:5,8-dimethanonaphthalene system. This strained substrate possessed a triflate leaving group to enhance its solvolytic reactivity. Detailed isotopic labeling and kinetic studies supported the generation of a symmetrical [C-F-C]+ bridge; interesting solution behavior allowed the manipulation of the rate-determining step for solvolysis depending on solvent nucleophilicity. After initial generation as a transient intermediate, the fluoronium ion was later produced as a stable species in solution and was fully characterized by 19F, 1H, and 13C NMR, with the resultant species displaying evident Cssymmetry through coordination of a molecule of SbF5. This remarkable ion proved stable to -30 °C. We also address a disagreement surrounding the nomenclature of fluoronium ions in particular and its potential impact upon the naming of onium ions in general. We strove to highlight the dangers of confusing the arbitrary concept of calculated partial charge with IUPAC nomenclature. Finally, we discuss future directions, for example, the synthesis of a fluoronium ion in which fluorine resides within an aromatic ring.

Arene Amination Instead of Fluorination: Substitution Pattern Governs the Reactivity of Dialkoxybenzenes with Selectfluor.

Arene substitution patterns are well-known to affect the regioselectivity of a given transformation but not necessarily the type of reactivity. Herein, we report that the substitution pattern of alkoxyarenes dictates whether a putative one-electron or two-electron reaction predominates in reactions with Selectfluor. A series of amination products is presented, resulting from the single-electron oxidation of electron-rich arenes followed by direct C-H to C-N bond formation. We demonstrate the ability of this transformation to synthesize medicinally and biologically relevant nitrogen heterocycles. Lastly, this unusual "mechanistic switch" is probed with computational chemistry and competition experiments.

Cooperative Noncovalent Interactions Lead to a Highly Diastereoselective Sulfonyl-Directed Fluorination of Steroidal α,ß-Unsaturated Hydrazones.

A series of steroidal α,ß-unsaturated hydrazones is presented whose behavior and reactivity are governed by various types of weak C-H hydrogen bonds. Several interesting features in a representative X-ray crystal structure and 1H NMR spectrum are examined that provide evidence for a unique bifurcated intramolecular C-H interaction. Moreover, these steroid derivatives undergo functionalization in the form of a highly regio- and stereoselective fluorination; the sulfonyl oxygen atoms are proposed to direct the fluorinating reagent through C-H hydrogen bonds.

Carbonyl-Directed Aliphatic Fluorination: A Special Type of Hydrogen Atom Transfer Beats Out Norrish II.

Recently, our group reported that enone and ketone functional groups, upon photoexcitation, can direct site-selective sp3 C-H fluorination in terpenoid derivatives. How this transformation actually occurred remained mysterious, as a significant number of mechanistic possibilities came to mind. Herein, we report a comprehensive study describing the reaction mechanism through kinetic studies, isotope-labeling experiments, 19F NMR, electrochemical studies, synthetic probes, and computational experiments. To our surprise, the mechanism suggests intermolecular hydrogen atom transfer (HAT) chemistry is at play, rather than classical Norrish hydrogen atom abstraction as initially conceived. What is more, we discovered a unique role for photopromoters such as benzil and related compounds that necessitates their chemical transformation through fluorination in order to be effective. Our findings provide documentation of an unusual form of directed HAT and are of crucial importance for defining the necessary parameters for the development of future methods.

Close Amide NH···F Hydrogen Bonding Interactions in 1,8-Disubstituted Naphthalenes.

In this note, we present a series of N-(8-fluoronaphthalen-1-yl)benzamide derivatives designed to maximize amide-NH···F hydrogen bond interactions therein. A combination of IR and NMR spectroscopy indicates a linear correlation between the high energy shift in NH stretching frequency and the electron withdrawing nature of the substituent, consistent with the trend predicted by DFT calculations. Additionally, a limiting case of hydrogen bonding is observed when the benzamide derivatives are replaced with trifluoroacetamide, causing an additional red shift of 44 cm-1 in the NH stretching frequency. Most importantly, 1H-19F coupling constants in this series are among the largest measured for amide-NH···F interactions. X-ray crystallography reveals face-to-face alignment of naphthalene rings in these derivatives resulting in part from the NH···F hydrogen bonds. This motif also dictates the formation of sheets composed of stacked naphthalene rings in the crystal structure as opposed to unfluorinated analogues wherein NH···OC hydrogen-bonding interactions force benzamide and naphthalene rings to engage in T-shaped π-π interactions instead. Additionally, the NH proton in the trifluoroacetamide derivative engages in extended H-bond interactions in its crystal structure.

DFT Case Study of the Mechanism of a Metal-Free Oxygen Atom Insertion into a p-Quinone Methide C(sp3)-C(sp2) Bond.

The site-selective introduction of an oxygen atom into an organic molecule, without the assistance of metals, is a useful transformation, though understanding the mechanistic underpinning of such a process is oftentimes a challenging task. In exploring this chemical space and in building upon experimental precedents, we have utilized computational tools to delineate the mechanistic details of site-selective oxygen atom insertion into a p-quinone methide C(sp3)-C(sp2) bond. To this end, several different reaction pathways for oxygen atom insertion were explored-each encompassing a unique element qualifying the respective pathway as being more or less feasible. The findings of these investigations revealed several features that were vital to this reactivity, including the formation of a dimeric intermediate, interconversion between ground- and excited-state species, and strain. Notably, the latter finding adds to the portfolio of strain-release-driven reactions that have emerged as popular methods to achieve otherwise difficult chemical transformations.

Site-Selective Photochemical Fluorination of Ketals: Unanticipated Outcomes in Selectivity and Stability.

We report a method for the regioselective photochemical sp3 C-H fluorination of acetonide ketals that presents interesting problems in chemical reactivity. The question of why certain products of the reaction are stable while others are not is addressed, as is the question of why only select α-ethereal hydrogen atoms are targeted in the reaction. We demonstrate that the method can be employed to synthesize unprecedented fluorinated sugars and steroids, and it can also be applied toward the fluorination of carbamates. Though some substrates contain up to eight discrete α-ethereal C-H bonds, we observed site-selectivity in each case, prompting us to investigate potential transition states for the reaction. Finally, a remarkable regiochemical switch upon minor structural modification of a diketal is also analyzed.

Switching a HO···π Interaction to a Nonconventional OH···π Hydrogen Bond: A Completed Crystallographic Puzzle.

In this article, we present crystallographic and spectroscopic evidence of a tunable system wherein a HO···π interaction switches incrementally to a nonconventional OH···π hydrogen bonding (HB) interaction. More specifically, we report the synthesis of substituted forms of model system 1 to study the effects of aryl ring electronic density on the qualitative characteristics of OH···π hydrogen bonds therein. The OH stretch in experimental infrared data, in agreement with density-functional theory (DFT) calculations, shows continuous red-shifts as the adjacent ring becomes more electron rich. For example, the OH stretch of an amino-substituted analogue is red-shifted by roughly 50 cm-1 compared to the same stretch in the CF3 analogue, indicating a significantly stronger HB interaction in the former. Moreover, DFT calculations (ωB97XD/6-311+G**) predict that increasing electronic density on the adjacent top ring reduces the aryl π-OH σ* energy gap with a concomitant enhancement of the OH n-π* energy gap. Consequently, a dominant π-σ* interaction in the amino substituted analogue locks the system in the in-form while a favorable n-π* interaction reverses the orientation of the oxygen-bound hydrogen in its protonated form. Additionally, the 1H NMR data of various analogues reveal that stronger OH···π interactions in systems with electron-rich aromatic rings slow exchange of the alcoholic proton, thereby revealing coupling with the geminal proton. Finally, X-ray crystallographic analyses of a spectrum of analogues clearly visualize the three distinct stages of "switch"-starting with exclusive HO···π, to partitioned HO···π/OH···π, and finally to achieving exclusive OH···π forms. Furthermore, the crystal structure of the amino analogue reveals an interesting feature in which an extended HB network, involving two conventional (NH···O) and two nonconventional (OH···π) HBs, dimerizes and anchors the molecule in the unit cell.

A Protonated Quinone Methide Stabilized by a Combination of Partial Aromatization and π-Interaction: Spectroscopic and Crystallographic Analysis.

We have expanded the repertoire of cation-π interactions to include a carbocation-π system resulting from the protonation of a π-stacked para-quinone methide (p-QM). This unusual carbocation is stabilized by a combination of partial aromatization of the QM moiety and through-space interaction with the π-system of the adjacent aromatic ring. Single crystal X-ray analysis of the protonated form reveals a structure consisting of a hydrogen-bound complex involving two molecules of the precursor and one proton.