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1.
J Org Chem ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031800

RESUMO

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.

2.
Acc Chem Res ; 53(1): 265-275, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877026

RESUMO

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.

6.
J Org Chem ; 84(21): 14349-14353, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31577426

RESUMO

We report an unprecedented photochemical oxygen insertion reaction into an aromatic quinone methide. Insertion happens specifically within a C(aryl)-C(alkyl) bond, whereas the quinone methide moiety remains intact itself. Detailed mechanistic studies, supported by DFT calculations, support a pathway in which the p-QM plays a pivotal activating role.

7.
Phys Chem Chem Phys ; 21(33): 18310-18315, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31397463

RESUMO

Quadrupole-bound anions are negative ions in which their excess electrons are loosely bound by long-range electron-quadrupole attractions. Experimental evidence for quadrupole-bound anions has been scarce; until now, only trans-succinonitrile had been experimentally confirmed to form a quadrupole-bound anion. In this study, we present experimental evidence for a new quadrupole-bound anion. Our combined Rydberg electron transfer/anion photoelectron spectroscopy study demonstrates that the ee conformer of 1,4-dicyanocyclohexane (DCCH) supports a quadrupole-bound anion state, and that the cis-DCCH conformer forms a dipole-bound anion state. The electron binding energies of the quadrupole- and dipole-bound anions are measured as 18 and 115 meV, respectively, both of which are in excellent agreement with theoretical calculations by Sommerfeld.

8.
J Org Chem ; 84(12): 8284-8288, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117575

RESUMO

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.

9.
Phys Chem Chem Phys ; 21(26): 14440-14452, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30920561

RESUMO

Bis(bithienyl)-1,2-dicyanoethene (4TCE) is a photoswitch that operates via reversible E/Z photoisomerization following absorption of visible light. cis-to-trans photoisomerization of 4TCE requires excitation below 470 nm, is relatively inefficient (quantum yield < 5%) and occurs via the lowest-lying triplet. We present excitation-wavelength dependent (565-420 nm) transient absorption (TA) studies to probe the photophysics of cis-to-trans isomerization to identify sources of switching inefficiency. TA data reveals contributions from more than one switch conformer and relaxation cascades between multiple states. Fast (∼4 ps) and slow (∼40 ps) components of spectral dynamics observed at low excitation energies (>470 nm) are readily attributed to deactivation of two conformers; this assignment is supported by computed thermal populations and absorption strengths of two molecular geometries (PA and PB) characterized by roughly parallel dipoles for the thiophenes on opposite sides of the ethene bond. Only the PB conformer is found to contribute to triplet population and the switching of cis-4TCE: high-energy excitation (<470 nm) of PB involves direct excitation to S2, relaxation from which prepares an ISC-active S1 geometry (ISC QY 0.4-0.67, kISC∼ 1.6-2.6 × 10-9 s-1) that is the gateway to triplet population and isomerization. We ascribe low cis-to-trans isomerization yield to excitation of the nonreactive PA conformer (75-85% loss) as well as loses along the PB S2→ S1→ T1 cascade (10-20% loss). In contrast, electrocyclization is inhibited by the electronic character of the excited states, as well as a non-existent thermal population of a reactive "antiparallel" ring conformation.

10.
Org Lett ; 21(7): 2326-2329, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30859826

RESUMO

We report the serendipitous synthesis of an indefinitely solution-stable ring-unsubstituted aliphatic p-quinone methide (p-QM) and detail its remarkable reaction chemistry through three archetypical chemical transformations: hydrogenation, hydride reduction, and nucleophilic addition. For example, the p-QM hydrogenates in a counterintuitive way; it resists all attempts at aromatization by catalytic reduction. Paradoxically, it does undergo aromatization/rearrangement upon reduction with LiAlH4. Nucleophilic addition of thiol results in an unanticipated rearrangement instead of the expected 1,6-conjugate addition. We hope that this highly stable p-QM and its unique reactivity provide some new insights into the chemistry of this important class of organic molecules.

11.
J Org Chem ; 83(23): 14234-14244, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30418026

RESUMO

The halofunctionalization of alkene substrates remains an essential tool for synthetic chemists. Herein, we report regioselective ammoniofluorination of unactivated alkenes through photochemical means. A one-pot transformation of the ammonium fluoride products into pharmaceutically relevant ß-fluoropiperazines is highlighted. Furthermore, a substrate-guided reactivity switch is observed: certain alkenes are shown to react with the same fluorinating reagent to instead give the less-substituted fluoride. We hope that the ammoniofluorination reaction will be of utility in the area of medicinal chemistry, where nitrogen and fluorine are among the most important heteroatoms.

12.
J Org Chem ; 83(16): 8803-8814, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29894188

RESUMO

In the last six years, the direct functionalization of aliphatic C-H (and C-C) bonds through user-friendly, radical-based fluorination reactions has emerged as an exciting research area in fluorine chemistry. Considering the historical narratives about the challenges of developing practical radical fluorination in organic frameworks, notable advancements in controlling both reactivity and selectivity have been achieved during this time. As one of the participants in the field, herein, we a provide brief account of research efforts in our laboratory from the initial discovery of radical monofluorination on unactivated C-H bonds in 2012 to more useful strategies to install fluorine on biologically relevant molecules through directed fluorination methods. In addition, accompanying mechanistic studies that have helped guide reaction design are highlighted in context.

13.
Angew Chem Int Ed Engl ; 57(7): 1924-1927, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29316122

RESUMO

We report the first spectroscopic evidence for a [C-F-C]+ fluoronium ion in solution. Extensive NMR studies (19 F, 1 H, 13 C) characterize a symmetric cage-like species in which fluorine exhibits substantial covalent bonding to each of the two carbon atoms involved in the three-center interaction. Experimental NMR data comport well with calculated values to lend credence to the structural assignment. As the culminating experiment, a Saunders isotopic perturbation test confirmed the symmetric structure. Congruent with the trend in other types of onium ions, the calculated charge at fluorine moves in a more positive (less negative) direction from the neutral. It is this important trend that explains in part the extraordinary historical difficulty in making theoretical predictions of fluoronium ions come true in solution, and why it takes fluorine captured in a cage to produce, finally, a stable ion and complete the historical arc of the organic halonium ion story.

14.
J Org Chem ; 83(3): 1565-1575, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29293338

RESUMO

In our continued effort to address the challenges of selective sp3 C-H fluorination on complex molecules, we report a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensitized approach is mild, simple to set up, and an economical alternative to our previous protocol based on direct excitation using UV light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary evidence for electron-transfer processes are highlighted.

15.
Angew Chem Int Ed Engl ; 57(11): 2758-2766, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29141116

RESUMO

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 covalent interactions of fluorine are also explored: the cage can close to form the first solution-phase C-F-C fluoronium ion.

16.
Chem Sci ; 8(10): 6918-6923, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29147517

RESUMO

The ubiquitous ketone carbonyl group generally deactivates substrates toward radical-based fluorinations, especially sites closest to it. Herein, ketones are used instead to direct aliphatic fluorination using Selectfluor, catalytic benzil, and visible light. Selective ß- and γ-fluorination are demonstrated on rigid mono-, di-, tri-, and tetracyclic (steroidal) substrates employing both cyclic and exocyclic aliphatic ketones as directing groups.

17.
J Am Chem Soc ; 139(42): 14913-14916, 2017 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-28992687

RESUMO

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.

18.
J Am Chem Soc ; 139(6): 2208-2211, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28146358

RESUMO

In the realm of aliphatic fluorination, the problem of reactivity has been very successfully addressed in recent years. In contrast, the associated problem of selectivity, that is, directing fluorination to specific sites in complex molecules, remains a great, fundamental challenge. In this report, we show that the enone functional group, upon photoexcitation, provides a solution. Based solely on orientation of the oxygen atom, site-selective photochemical fluorination is achieved on steroids and bioactive polycycles with up to 65 different sp3 C-H bonds. We have also found that γ-, ß-, homoallylic, and allylic fluorination are all possible and predictable through the theoretical modes reported herein. Lastly, we present a preliminary mechanistic hypothesis characterized by intramolecular hydrogen atom transfer, radical fluorination, and ultimate restoration of the enone. In all, these results provide a leap forward in the design of selective fluorination of complex substrates that should be relevant to drug discovery, where fluorine plays a prominent role.


Assuntos
Hidrocarbonetos Fluorados/síntese química , Cetonas/química , Compostos Policíclicos/química , Terpenos/química , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Processos Fotoquímicos
19.
J Org Chem ; 82(7): 3996-4000, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28240908

RESUMO

An unprecedented intermolecular aliphatic C-F···H-C interaction was observed in the X-ray crystal structure of a fluorinated triterpenoid. Despite the notion of fluorine being a poor acceptor, computational and IR studies revealed this interaction to be a weak to moderate hydrogen bond with a C-H stretch vibration frequency blue-shifted by 14 cm-1 and d(F-H) = 2.13 Å. In addition, the aliphatic C-F bond is the preferred acceptor in the presence of multiple, traditionally stronger oxygen-based hydrogen bond acceptors.

20.
J Org Chem ; 81(17): 8087-90, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27467448

RESUMO

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.

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