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The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF5-CBs) are now synthetically accessible through strain-release functionalization of [1.1.0]bicyclobutanes (BCBs) using SF5Cl. Methods for both chloropentafluorosulfanylation and hydropentafluorosulfanylation of sulfone-based BCBs are detailed herein, as well as proof-of-concept that the logic extends to tetrafluoro(aryl)sulfanylation, tetrafluoro(trifluoromethyl)sulfanylation, and three-component pentafluorosulfanylation reactions. The methods presented enable isolation of both syn and anti isomers of SF5-CBs, but we also demonstrate that this innate selectivity can be overridden in chloropentafluorosulfanylation; that is, an anti-stereoselective variant of SF5Cl addition across sulfone-based BCBs can be achieved by using inexpensive copper salt additives. Considering the SF5 group and CBs have been employed individually as nonclassical bioisosteres, structural aspects of these unique SF5-CB "hybrid isosteres" were then contextualized using SC-XRD. From a mechanistic standpoint, chloropentafluorosulfanylation ostensibly proceeds through a curious polarity mismatch addition of electrophilic SF5 radicals to the electrophilic sites of the BCBs. Upon examining carbonyl-containing BCBs, we also observed rare instances whereby radical addition to the 1-position of a BCB occurs. The nature of the key C(sp3)-SF5 bond formation step - among other mechanistic features of the methods we disclose - was investigated experimentally and with DFT calculations. Lastly, we demonstrate compatibility of SF5-CBs with various downstream functionalizations.
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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.
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BACKGROUND: Performing lumbar punctures carries a risk of harm to the patient, but the information cerebrospinal fluid provides often makes this procedure necessary. Clinicians in the Australian setting would benefit from having more information on these procedures, in order to help them in a risk versus benefit analysis. AIMS: To describe the contemporary indications, cerebrospinal fluid findings and complications of lumbar punctures in a metropolitan Australian health service. METHODS: Retrospective electronic medical records audit of lumbar punctures performed on 525 adults within three acute hospitals between 1 July 2018 and 30 June 2019. Main outcome measures include frequency of indication for lumbar puncture by category, normal versus abnormal cerebrospinal fluid for each category, and frequency, severity and type of complications of lumbar punctures. RESULTS: Of 525 adult lumbar punctures that were assessed in this study, 466 were performed for a diagnostic indication. The most common diagnostic indications were acute severe headache (156 procedures; 33.5%) and encephalopathy (128 procedures; 27.5%). The yield of abnormal results varied by indication category, with the above indications yielding abnormal results in 85 (54.5%) and 72 (56.3%) cases respectively. A complication was recorded in 54 (10.3% of total) procedures. The majority (45; 8.6%) of complications were minor in severity and most frequently consisted of post-dural puncture headache (PDPH). CONCLUSIONS: In the era of an increased reliance on high quality neuroimaging, lumbar puncture has a high diagnostic yield with a low rate of major complications. The most common complication is PDPH, which is mild and self-limiting in most cases.
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Cefalea Pospunción de la Duramadre , Punción Espinal , Adulto , Humanos , Punción Espinal/efectos adversos , Estudios Retrospectivos , Australia/epidemiología , Cefalea Pospunción de la Duramadre/etiología , Cefalea Pospunción de la Duramadre/complicaciones , Cefalea/etiologíaRESUMEN
Total synthesis-the ultimate proving ground for the invention and field-testing of new methods, exploration of disruptive strategies, final structure confirmation, and empowerment of medicinal chemistry on natural products-is one of the oldest and most enduring subfields of organic chemistry. In the early days of this field, its sole emphasis focused on debunking the concept of vitalism, that living organisms could create forms of matter accessible only to them. Emphasis then turned to the use of synthesis to degrade and reconstitute natural products to establish structure and answer questions about biosynthesis. It then evolved to not only an intricate science but also a celebrated form of art. As the field progressed, a more orderly and logical approach emerged that served to standardize the process. These developments even opened up the possibility of computer-aided design using retrosynthetic analysis. Finally, the elevation of this field to even higher levels of sophistication showed that it was feasible to synthesize any natural product, regardless of complexity, in a laboratory. During this remarkable evolution, as has been reviewed elsewhere, many of the principles and methods of organic synthesis were refined and galvanized. In the modern era, students and practitioners are still magnetically attracted to this field due to the excitement of the journey, the exhilaration of creation, and the opportunity to invent solutions to challenges that still persist. Contemporary total synthesis is less concerned with demonstrating a proof of concept or a feasible approach but rather aims for increased efficiency, scalability, and even "ideality." In general, the molecules of Nature are created biosynthetically with levels of practicality that are still unimaginable using the tools of modern synthesis. Thus, as the community strives to do more with less (i.e., innovation), total synthesis is now focused on a pursuit for simplicity rather than a competition for maximal complexity. In doing so, the practitioner must devise outside-the-box strategies supplemented with forgotten or newly invented methods to reduce step count and increase the overall economy of the approach. The downstream applications of this pursuit not only empower students who often go on to apply these skills in the private sector but also lead to new discoveries that can impact numerous disciplines of societal importance. This account traces some select case studies from our laboratory over the past five years that vividly demonstrate our own motivation for dedicating so much effort to this classic field. In aiming for simplicity, we focus on the elusive goal of achieving ideality, a term that, when taken in the proper context, can serve as a guiding light to point the way to furthering progress in organic synthesis.
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Productos Biológicos/síntesis química , Alcaloides/síntesis química , Alcaloides/química , Antibacterianos/síntesis química , Antibacterianos/química , Productos Biológicos/química , Oligopéptidos/síntesis química , Oligopéptidos/química , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Técnicas de Síntesis en Fase Sólida , Tiazolidinas/síntesis química , Tiazolidinas/química , Ubiquinona/análogos & derivados , Ubiquinona/síntesis química , Ubiquinona/químicaRESUMEN
In synthetic method development, the most rewarding path is seldom a straight line. While our initial entry into pentafluorosulfanyl (SF5 ) chemistry did not go according to plan (due to inaccessibility of reagents such as SF5 Cl at the time), a "detour" led us to establish mild and inexpensive oxidative fluorination conditions that made aryl-SF5 compound synthesis more accessible. The method involved the use of potassium fluoride and trichloroisocyanuric acid (TCICA)-a common swimming pool disinfectant-as opposed to previously employed reagents such as F2 , XeF2 , HF, and Cl2 . Thereafter, curiosity led us to explore applications of TCICA/KF as a more general approach to the synthesis of fluorinated Group 15, 16, and 17 heteroatoms in organic scaffolds; this, in turn, prompted SC-XRD, VT-NMR, computational, and physical organic studies. Ultimately, it was discovered that TCICA/KF can be used to synthesize SF5 Cl, enabling SF5 chemistry in an unexpected way.
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Fluoruros , Halogenación , Fluoruros/química , Indicadores y Reactivos , Estrés Oxidativo , Compuestos de Potasio , TriazinasRESUMEN
The fundamental challenge of C-F bond formation by reductive elimination has been met by compounds of select transition metals and fewer main group elements. The work detailed herein expands the list of main group elements known to be capable of reductively eliminating a C-F bond to include tellurium. Surprising and novel modes of both sp2 and sp3 C-F bond formation were observed alongside formation of TeIV cations during two separate attempts to synthesize/characterize fluorinated organotellurium(VI) cations in superacidic media (SbF5 /SO2 ClF). Following detailed low-temperature NMR experiments, the mechanisms of the two unique reductive elimination reactions were probed and investigated using density functional theory (DFT) calculations. Ultimately, we found that an "indirect" reductive elimination pathway is likely operative whereby Sb plays a key role in fluoride abstraction and C-F bond formation, as opposed to unimolecular reductive elimination from a discrete TeVI cation.
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We leveraged the recent increase in synthetic accessibility of SF5 Cl and Ar-SF4 Cl compounds to combine chemistry of the SF5 and SF4 Ar groups with strain-release functionalization. By effectively adding SF5 and SF4 Ar radicals across [1.1.1]propellane, we accessed structurally unique bicyclopentanes, bearing two distinct elements of bioisosterism. Upon evaluating these "hybrid isostere" motifs in the solid state, we measured exceptionally short transannular distances; in one case, the distance rivals the shortest nonbonding Câ â â C contact reported to date. This prompted SC-XRD and DFT analyses that support the notion that a donor-acceptor interaction involving the "wing" C-C bonds is playing an important role in stabilization. Thus, these heretofore unknown structures expand the palette for highly coveted three-dimensional fluorinated building blocks and provide insight to a more general effect observed in bicyclopentanes.
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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.
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The analysis of crystal structures of SF5 - or SF4 -containing molecules revealed that these groups are often surrounded by hydrogen or other fluorine atoms. Even though fluorine prefers Fâ â â H over Fâ â â F contacts, the latter appeared to be important in many compounds. In a significant number of datasets, the closest Fâ â â F contacts are below 95 % of the van der Waals distance of two F atoms. Moreover, a number of repeating structural motifs formed by contacts between SF5 groups was identified, including different supramolecular dimers and infinite chains. Among SF4 -containing molecules, the study focused on SF4 Cl compounds, including the first solid-state structure analyses of these reactive species. Additionally, electrostatic potential surfaces of a series of Ph-SF5 derivatives were calculated, pointing out the substituent influence on the ability of Fâ â â X contact formation (X=F or other electronegative atom). Interaction energies were calculated for different dimeric arrangements of Ph-SF5 , which were extracted from experimental crystal structure determinations.
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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.
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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.
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Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1)â occasional handling of toxic or pyrophoric PIII starting materials and 2)â 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)â new difluorophosphonium ions, 2)â hexafluorophosphate salts, and 3)â fluorinated antimony- and arsenic- compounds.
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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.
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Modern pentafluorosulfanyl (SF5 ) chemistry has an Achilles heel: synthetic accessibility. Herein, we present the first approach to aryl-SF4 Cl compounds (key intermediates in state-of-the-art aryl-SF5 synthesis) that overcomes the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl2 ) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride, and catalytic amounts of acid. These simple, mild conditions allow direct access to aryl-SF4 Cl intermediates that either have not been or cannot be demonstrated using previous methods. Furthermore, the same approach provides access to aryl-SF3 and aryl-SeF3 compounds, which extend the applications of this chemistry beyond arene SF5 -functionalization, and demonstrate its ability to address a more general oxidative fluorination problem.
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The TCICA/KF approach to oxidative fluorination of heteroatoms has emerged as a surprisingly simple, safe, and versatile surrogate to classically challenging fluorination reactions. Although polyfluorination (or chlorofluorination) of diaryl disulfides, diaryl diselenides, diaryl ditellurides, aryl iodides, and aryl(perfluoroalkyl)tellanes has been described, the application of this TCICA/KF methodology to aryl(perfluoroalkyl)sulfanes and selanes remains an area of unexplored chemical space. Accordingly, to address the "missing links" in the developing series of chalcogen-based substrate reactivity, we report mild syntheses of metastable difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and selanes. As only limited examples of these species exist in the current literature (accessible only by using F2 or XeF2 /HF), we have carried out detailed structural analyses, primarily using NMR and SC-XRD data. In addition, we investigate the effect of the perfluoroalkyl chain on the outcome of oxidative fluorination, and, finally, we provide preliminary evidence that difluoro(aryl)(trifluoro-methyl)-λ4 -sulfanes may act as fluorinating reagents.
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The TeF5 group is significantly underexplored as a highly fluorinated substituent on an organic framework, despite it being a larger congener of the acclaimed SF5 group. In fact, only one aryl-TeF5 compound (phenyl-TeF5 ) has been reported to date, synthesized using XeF2 . Our recently developed mild TCICA/KF approach to oxidative fluorination provides an affordable and scalable alternative to XeF2 . Using this method, we report a scope of extensively characterized aryl-TeF5 compounds, along with the first SC-XRD data on this compound class. The methodology was also extended to the synthesis and structural study of heretofore unknown aryl-TeF4 CF3 compounds. Additionally, preliminary reactivity studies unveiled some inconsistencies with previous literature regarding phenyl-TeF5 . Although our studies conclude that the arene-based TeF5 (and TeF4 CF3 ) group is not quite as robust as the SF5 group, we find that the TeF5 group is more stable than previously thought, thus opening a door to explore new applications of this motif.
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Isquemia Encefálica , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Terapia Trombolítica , Anticoagulantes/uso terapéutico , Fibrinolíticos/uso terapéutico , Resultado del TratamientoRESUMEN
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.
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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.
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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.