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.

Rapid GSH detection and versatile peptide/protein labelling to track cell penetration using coumarin-based probes.

Biothiols play essential roles in balancing the redox state and modulating cellular functions. Fluorescent probes for monitoring/labelling biothiols often suffer from slow reaction rates, strong background fluorescence and cytotoxic byproduct release. Thus, developing facile and versatile probes to overcome the challenges is still in high demand. Here, we report four coumarin-maleimides as fast responding and fluorogenic probes to detect GSH or label peptides/proteins. The probes quantitatively and selectively react with GSH via Michael addition within 1-2 min, achieving an 11-196-fold increase in fluorescence quantum yield via blockage of the photoinduced electron transfer (PET) process. Optimized probe 4 is applied for the detection of GSH in vitro (A549 cells) and in vivo (zebrafish embryos). Taking advantage of the fast Michael addition between the maleimide moiety and the sulfhydryl group, we expand the application of our method for fluorescent labelling of peptides/proteins and for tracking their cellular uptake process. The labelling strategy works for both Cys-bearing and Cys-free proteins after the introduction of a sulfhydryl group using Traut's reagent. Fluorescence assay reveals that the TAT-peptide can efficiently enter cells, but H3 protein, part of nucleosomes, prefers to bind on the cell membrane by electrostatic interactions, shedding light on the cellular uptake activity of nucleosomes and affording a potential membrane staining strategy. Overall, our study illustrates the broad potential of coumarin-maleimide based dual-functional probes for GSH detection and versatile protein labelling in biochemical research.

Tricyclic Aza-Andrographolide Derivatives from Late-Stage Hydroamination and Their Anti-human Coronavirus (Anti-HCoV) Activity.

A late-stage functionalization (LSF) of the natural product andrographolide for the efficient assembly of a range of structurally interesting and diverse tricyclic-aza derivatives was developed. The key to the diversification is a photo-catalyzed intramolecular hydroamination reaction, and acridinium derivatives were demonstrated to be the optimal catalysts. Additionally, the synthesized tricyclic aza-andrographolide derivatives were found to inhibit human coronavirus with high potency.

Combining visible-light induction and copper catalysis for chemo-selective nitrene transfer for late-stage amination of natural products.

Nitrene transfer chemistry is an effective strategy for introducing C-N bonds, which are ubiquitous in pharmaceuticals, agrochemicals and diverse bioactive natural products. The development of chemical methodology that can functionalize unique sites within natural products through nitrene transfer remains a challenge in the field. Herein, we developed copper catalyzed chemoselective allylic C-H amination and catalyst-free visible-light induced aziridination of alkenes through nitrene transfer. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Furthermore, combination of these two methods enable the intermolecular chemo-selective late-stage amination of biologically active natural products, leading to C-H amination or C=C aziridination products in a tunable way. A series of control experiments indicate two-step radical processes were involved in both reaction systems.

Deoxygenative Fluorination of Phosphine Oxides: A General Route to Fluorinated Organophosphorus(V) Compounds and Beyond.

Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1) occasional handling of toxic or pyrophoric PIII starting materials and 2) a dependence on hazardous fluorinating reagents such as XeF2 . Herein, we present a simple solution and introduce a deoxygenative fluorination (DOF) approach that utilizes easy-to-handle phosphine oxides as starting materials and effectively replaces harsh fluorinating reagents by a combination of oxalyl chloride and potassium fluoride. The reaction has proven to be general, as R3 PF2 , R2 PF3 , and RPF4 compounds (as well as various cations and anions derived from these) are accessible in good yields and on up to a multi-gram scale. DFT calculations were used to bolster our observations. Notably, the discovery of this new method led to a convenient synthesis of 1) new difluorophosphonium ions, 2) hexafluorophosphate salts, and 3) fluorinated antimony- and arsenic- compounds.

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.

Through-Space Activation Can Override Substituent Effects in Electrophilic Aromatic Substitution.

Electrophilic aromatic substitution (EAS) represents one of the most important classes of reactions in all of chemistry. One of the "iron laws" of EAS is that an electron-rich aromatic ring will react more rapidly than an electron-poor ring with suitable electrophiles. In this report, we present unique examples of electron-deficient arenes instead undergoing preferential substitution in intramolecular competition with more electron-rich rings. These results were made possible by exploiting the heretofore unknown propensity of a hydrogen-bonding OH-arene interaction to switch to the alternative HO-arene interaction in order to provide activation. In an extreme case, this through-space HO-arene activation is demonstrated to overcome the deactivating effect of a trifluoromethyl substituent, making an otherwise highly electron-deficient ring the site of exclusive reactivity in competition experiments. Additionally, the HO-arene activation promotes tetrabromination of an increasingly more electron-deficient arene before the unactivated "control" ring undergoes monobromination. It is our hope that these results will shed light on biological interactions as well as provide new strategies for the electrophilic substitution of aromatic rings.

A C-F Bond Directed Diels-Alder Reaction.

We demonstrate a C-F bond driven Diels-Alder reaction of a fluorinated dienophile and a borole that shows remarkable diastereoselectivity. The product's structure was confirmed by X-ray crystallography, revealing an unusual conformation featuring a hypercoordinate boron. Calculations suggest that a B···F interaction instigates the reaction chemistry, the magnitude of which is maximized in the transition state-in essence, the B···F distance "yo-yos" from long to short in the transition state and back again to long in the product.

The origins of the directionality of noncovalent intermolecular interactions.

The recent σ-hole concept emphasizes the contribution of electrostatic attraction to noncovalent bonds, and implies that the electrostatic force has an angular dependency. Here a set of clusters, which includes hydrogen bonding, halogen bonding, chalcogen bonding, and pnicogen bonding systems, is investigated to probe the magnitude of covalency and its contribution to the directionality in noncovalent bonding. The study is based on the block-localized wavefunction (BLW) method that decomposes the binding energy into the steric and the charge transfer (CT) (hyperconjugation) contributions. One unique feature of the BLW method is its capability to derive optimal geometries with only steric effect taken into account, while excluding the CT interaction. The results reveal that the overall steric energy exhibits angular dependency notably in halogen bonding, chalcogen bonding, and pnicogen bonding systems. Turning on the CT interactions further shortens the intermolecular distances. This bond shortening enhances the Pauli repulsion, which in turn offsets the electrostatic attraction, such that in the final sum, the contribution of the steric effect to bonding is diminished, leaving the CT to dominate the binding energy. In several other systems particularly hydrogen bonding systems, the steric effect nevertheless still plays the major role whereas the CT interaction is minor. However, in all cases, the CT exhibits strong directionality, suggesting that the linearity or near linearity of noncovalent bonds is largely governed by the charge-transfer interaction whose magnitude determines the covalency in noncovalent bonds.

Deprotonation of methyl-substituted, five-membered aromatic molecules: a surprising case of mixed conjugation, rehybridization, and induction contributions.

Methyl-substituted, six-membered aromatic molecules are deprotonated to benzylic carbanions, which are stabilized by π conjugation. In contrast, deprotonation of 3(5)-methylpyrazole (NH protected) occurs at an endocylic CH group. Computational analyses showed that the reduction of π conjugation in substituted five-membered rings plays a major role, while the reduced bond angles, in addition to the strengthened induction of Csp(2) versus Csp(3), further favor the deprotonation of endocyclic carbon sites rather than that of the methyl group.

On the nature of blueshifting hydrogen bonds.

The block-localized wave function (BLW) method can derive the energetic, geometrical, and spectral changes with the deactivation of electron delocalization, and thus provide a unique way to elucidate the origin of improper, blueshifting hydrogen bonds versus proper, redshifting hydrogen bonds. A detailed analysis of the interactions of F(3)CH with NH(3) and OH(2) shows that blueshifting is a long-range phenomenon. Since among the various energy components contributing to hydrogen bonds, only the electrostatic interaction has long-range characteristics, we conclude that the contraction and blueshifting of a hydrogen bond is largely caused by electrostatic interactions. On the other hand, lengthening and redshifting is primarily due to the short-range n(Y)→σ*(X-H) hyperconjugation. The competition between these two opposing factors determines the final frequency change direction, for example, redshifting in F(3)CH⋅⋅⋅NH(3) and blueshifting in F(3)CH⋅⋅⋅OH(2). This mechanism works well in the series F(n)Cl(3)-n CH⋅⋅⋅Y (n=0-3, Y=NH(3), OH(2), SH(2)) and other systems. One exception is the complex of water and benzene. We observe the lengthening and redshifting of the O-H bond of water even with the electron transfer between benzene and water completely quenched. A distance-dependent analysis for this system reveals that the long-range electrostatic interaction is again responsible for the initial lengthening and redshifting.

Electron transfer in pnicogen bonds.

As a new type of noncovalent interactions, pnicogen bond between a VA group element (N, P, and As) and an electron donor (Lewis base) has grabbed attention in recent several years. Here we employ the block-localized wave function (BLW) based energy decomposition scheme to probe the bonding nature in a series of substituted phosphines X(n)PH(3-n) complexed with ammonia. As the BLW method can derive the optimal monomer orbitals in a complex with the electron transfer among monomers quenched, we can effectively examine the HOMO-LUMO interaction in these pnicogen bonding systems. Among various energy components, electron transfer energy together with the polarization energy dominates the pnicogen bonding energy. Although usually it is assumed that the electron transfer from ammonia to substituted phosphines occurs in the form of n → σ*(XP) hyperconjugative interaction, we identify a kind of new pathway when X = NO2 and CN, i.e., n → dπ*, which results from the interaction between the π orbital of cyano or nitro substituent and d orbitals on P. But still this picture of electron transfer using a single pair of orbitals is greatly simplified, as the electron density difference (EDD) maps corresponding to the overall electron transfer processes show the accumulation of electron density on the P side opposite to the X-P bond, with insignificant or even negligible gain of electron density on the substituent group side. Thus, the EDD maps tend to support the concept of σ-hole in pnicogen bonds.