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1.
Org Lett ; 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39298654

RESUMEN

We have developed a dual-catalytic system capable of site-selective azidation of inert C(sp3)-H bonds with concomitant and modular anti-Markovnikov alkene fluoroalkylation. The protocol leverages the synergetic cooperation of both the photocatalyst and earth-abundant iron catalyst to deliver two radical species in succession to minimally functionalized alkenes. This powerful catalyst system exhibits broad scope, mild conditions, and excellent regioselectivity for a variety of substrates and fluoroalkyl fragments. The key to this C-centered radical relay is the matched rate of both photocatalytic and iron catalytic cycles, ensuring selective azidofluoroalkylation with a broad array of fluoroalkyl sources from trivial reagents.

2.
J Am Chem Soc ; 146(25): 17296-17310, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38875703

RESUMEN

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

3.
Chem Commun (Camb) ; 60(27): 3705-3708, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38477139

RESUMEN

C-N bonds play a critical role in pharmaceutical, agrochemical, and materials sciences, necessitating ever-better methods to forge this linkage. Here we report a simple procedure for direct C(sp3)-H azidation using iron or manganese catalysis and a nucleophilic azide source. All reagents are commercially available, the experimental procedure is simple, and we can use the C-H donor substrate as the limiting reagent, a challenge for many C-H azidation methods. Preliminary experiments are consistent with a hydrogen atom transfer (HAT)/radical ligand transfer (RLT) radical cascade mechanism and a wide variety of substrates can be azidated in moderate to high yields.

4.
Chem Sci ; 15(1): 124-133, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38131080

RESUMEN

Ligand-to-metal charge transfer (LMCT) is a mechanistic strategy that provides a powerful tool to access diverse open-shell species using earth abundant elements and has seen tremendous growth in recent years. However, among many reaction manifolds driven by LMCT reactivity, a general and catalytic protocol for modular difunctionalization of alkenes remains unknown. Leveraging the synergistic cooperation of iron-catalyzed ligand-to-metal charge transfer and radical ligand transfer (RLT), here we report a photocatalytic, modular difunctionalization of alkenes using inexpensive iron salts catalytically to function as both radical initiator and terminator. Additionally, strategic use of a fluorine atom transfer reagent allows for general fluorochlorination of alkenes, providing the first example of interhalogen compound formation using earth abundant element photocatalysis. Broad scope, mild conditions and versatility in converting orthogonal nucleophiles (TMSN3 and NaCl) directly into corresponding open-shell radical species are demonstrated in this study, providing a robust means towards accessing vicinal diazides and homo-/hetero-dihalides motifs catalytically. These functionalities are important precursors/intermediates in medicinal and material chemistry. Preliminary mechanistic studies support the radical nature of these transformations, disclosing the tandem LMCT/RLT as a powerful reaction manifold in catalytic olefin difunctionalization.

5.
Nat Chem ; 15(12): 1683-1692, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37957278

RESUMEN

Incorporation of fluoroalkyl motifs in pharmaceuticals can enhance the therapeutic profiles of the parent molecules. The hydrofluoroalkylation of alkenes has emerged as a promising route to diverse fluoroalkylated compounds; however, current methods require superstoichiometric oxidants, expensive/oxidative fluoroalkylating reagents and precious metals, and often exhibit limited scope, making a universal protocol that addresses these limitations highly desirable. Here we report the hydrofluoroalkylation of alkenes with cheap, abundant and available fluoroalkyl carboxylic acids as the sole reagents. Hydrotrifluoro-, difluoro-, monofluoro- and perfluoroalkylation are all demonstrated, with broad scope, mild conditions (redox neutral) and potential for late-stage modification of bioactive molecules. Critical to success is overcoming the exceedingly high redox potential of feedstock fluoroalkyl carboxylic acids such as trifluoroacetic acid by leveraging cooperative earth-abundant, inexpensive iron and redox-active thiol catalysis, enabling these reagents to be directly used as hydroperfluoroalkylation donors without pre-activation. Preliminary mechanistic studies support the radical nature of this cooperative process.

7.
Chem Catal ; 3(6)2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37720729

RESUMEN

Ligand-to-metal charge transfer (LMCT) using stoichiometric copper salts has recently been shown to permit decarboxylative C-N bond formation via an LMCT/radical polar crossover (RPC) mechanism; however, this method is unable to function catalytically and cannot successfully engage unactivated alkyl carboxylic acids, presenting challenges to the general applicability of this approach. Leveraging the concepts of ligand-to-metal charge transfer (LMCT) and radical-ligand-transfer (RLT), we herein report the first photochemical, iron-catalyzed direct decarboxylative azidation. Simply irradiating an inexpensive iron nitrate catalyst in the presence of azidotrimethylsilane allows for a diverse array of carboxylic acids to be converted to corresponding organic azides directly with broad functional group tolerance and mild conditions. Intriguingly, no additional external oxidant is required for this reaction to proceed, simplifying the reaction protocol. Finally, mechanistic studies are consistent with a radical mechanism and suggest that the nitrate counteranion serves as an internal oxidant for turnover of the iron catalyst.

8.
Beilstein J Org Chem ; 19: 1225-1233, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37614927

RESUMEN

The place of alkyl radicals in organic chemistry has changed markedly over the last several decades, evolving from challenging-to-generate "uncontrollable" species prone to side reactions to versatile reactive intermediates enabling construction of myriad C-C and C-X bonds. This maturation of free radical chemistry has been enabled by several advances, including the proliferation of efficient radical generation methods, such as hydrogen atom transfer (HAT), alkene addition, and decarboxylation. At least as important has been innovation in radical functionalization methods, including radical-polar crossover (RPC), enabling these intermediates to be engaged in productive and efficient bond-forming steps. However, direct engagement of alkyl radicals remains challenging. Among these functionalization approaches, a bio-inspired mechanistic paradigm known as radical ligand transfer (RLT) has emerged as a particularly promising and versatile means of forming new bonds catalytically to alkyl radicals. This development has been driven by several key features of RLT catalysis, including the ability to form diverse bonds (including C-X, C-N, and C-S), the use of simple earth abundant element catalysts, and the intrinsic compatibility of this approach with varied radical generation methods, including HAT, radical addition, and decarboxylation. Here, we provide an overview of the evolution of RLT catalysis from initial studies to recent advances and provide a conceptual framework we hope will inspire and enable future work using this versatile elementary step.

9.
Cell Rep Phys Sci ; 4(4)2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37235063

RESUMEN

Epoxide ring-opening reactions have long been utilized to furnish alcohol products that are valuable in many subfields of chemistry. While many epoxide-opening reactions are known, the hydrogenative opening of epoxides via ionic means remains challenging because of harsh conditions and reactive hydride nucleophiles. Recent progress has shown that radical chemistry can achieve hydrogenative epoxide ring opening under relatively mild conditions; however, these methods invariably require oxophilic metal catalysts and sensitive reagents. In response to these challenges, we report a new approach to epoxide ring-opening hydrogenation using bio-inspired Earth-abundant vitamin B12 and thiol-centric hydrogen atom transfer (HAT) co-catalysis to produce Markovnikov alcohols under visible light irradiation. This powerful reaction system exhibits a broad substrate scope, including a number of electrophilic and reductively labile functionalities that would otherwise be susceptible to reduction or cleavage by hydride nucleophiles, and preliminary mechanistic experiments are consistent with a radical process.

10.
Angew Chem Int Ed Engl ; 62(3): e202213055, 2023 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-36350328

RESUMEN

Decarboxylative protonation is a general deletion tactic to replace polar carboxylic acid groups with hydrogen or its isotope. Current methods rely on the pre-activation of acids, non-sustainable hydrogen sources, and/or expensive/highly oxidizing photocatalysts, presenting challenges to their wide adoption. Here we show that a cooperative iron/thiol catalyst system can readily achieve this transformation, hydrodecarboxylating a wide range of activated and unactivated carboxylic acids and overcoming scope limitations in previous direct methods. The reaction is readily scaled in batch configuration and can be directly performed in deuterated solvent to afford high yields of d-incorporated products with excellent isotope incorporation efficiency; characteristics not attainable in previous photocatalyzed approaches. Preliminary mechanistic studies indicate a radical mechanism and kinetic results of unactivated acids (KIE=1) are consistent with a light-limited reaction.

11.
Wellcome Open Res ; 8: 580, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38779057

RESUMEN

Background: Despite a growth in interest in recent years in the benefits of working co-creatively with the Arts for people living with dementia, little attention has been given to understanding the role of the professional artists within this context. Our main question here is 'How do professional artists apply their skills and knowledge in co-creative arts groups with people with dementia?' This paper has been informed by the insights gained from a series of conversations, observations and journals that were kept by four UK based artists (two musicians and two dancers) who reflexively interrogated what they were doing during the course of an 8-week co-creative arts project with people living with dementia. Methods: The research used an empirical case study methodology, with the authors adopting a thematic approach to the analysis of the data. Results: Thematic analysis resulted in three main themes: Authenticity, Enabling Risk and Togetherness. These themes characterise the skills, techniques and specialised knowledge used by the artists during the co-creative sessions. Conclusions: Following this analysis, the article argues that the beneficial effects for people living with dementia of co-creative art-based work come about through the conscious application by the artists of their shared skills and knowledge, acquired through training and ongoing artistic practice. Rather than an assumption that 'The Arts' are in themselves beneficial for people living with dementia, we must consider the active role played by the artists who are so integral to the process.

12.
Tetrahedron Lett ; 1182023 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-38505129

RESUMEN

Catalytic alkene hydrogenation is a powerful method that has been widely used in the syntheses of valuable products ranging from commodity chemicals to pharmaceuticals. Hydrogenation has also been a key strategy for selectively introducing heavy hydrogen isotopes to small molecules, a key strategy for metabolism studies and even the synthesis of "heavy drugs," where the hydrogen isotope is a key element of the active pharmaceutical ingredient. Traditional hydrogenations with pressurized H2 gas are atom economic but often require complex reaction setups or expensive metal catalysts. Further, use of diatomic hydrogen necessarily limits the ability to incorporate different hydrogen isotopes at each alkene position, with H2, D2, and T2 each resulting in compete labeling of the alkene. In response to these challenges, a recent and growing movement has sought to develop transfer hydrogenation methods using non-H2 hydrogen sources and earth abundant element catalysts to simplify reaction operation. Excitingly, recent developments have delivered transfer hydrogenations that proceed using cooperative hydrogen donor reagents, permitting the controllable incorporation of different hydrogen isotopes at each position of the alkene via reagent control. In this Digest, we disclose recent advances in Earth-abundant metal-catalyzed cooperative transfer hydrogenation of alkenes with various combinations of two distinct transfer hydrogen reagents as non-H2 hydrogen sources.

13.
Nat Commun ; 13(1): 7881, 2022 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-36564375

RESUMEN

Vicinal diamines are privileged synthetic motifs in chemistry due to their prevalence and powerful applications in bioactive molecules, pharmaceuticals, and ligand design for transition metals. With organic diazides being regarded as modular precursors to vicinal diamines, enormous efforts have been devoted to developing efficient strategies to access organic diazide generated from olefins, themselves common feedstock chemicals. However, state-of-the-art methods for alkene diazidation rely on the usage of corrosive and expensive oxidants or complicated electrochemical setups, significantly limiting the substrate tolerance and practicality of these methods on large scale. Toward overcoming these limitations, here we show a photochemical diazidation of alkenes via iron-mediated ligand-to-metal charge transfer (LMCT) and radical ligand transfer (RLT). Leveraging the merger of these two reaction manifolds, we utilize a stable, earth abundant, and inexpensive iron salt to function as both radical initiator and terminator. Mild conditions, broad alkene scope and amenability to continuous-flow chemistry rendering the transformation photocatalytic were demonstrated. Preliminary mechanistic studies support the radical nature of the cooperative process in the photochemical diazidation, revealing this approach to be a powerful means of olefin difunctionalization.


Asunto(s)
Alquenos , Hierro , Alquenos/química , Ligandos , Catálisis , Hierro/química , Diaminas
14.
J Am Chem Soc ; 144(26): 11810-11821, 2022 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-35729791

RESUMEN

Development of visible light-mediated atom transfer radical addition of haloalkanes onto unsaturated hydrocarbons has seen rapid growth in recent years. However, due to its radical chain propagation mechanism, diverse functionality other than the pre-existing (pseudo-)halide on the alkyl halide source cannot be incorporated into target molecules in a one-step, economic fashion. Inspired by the prominent reactivities shown by cytochrome P450 hydroxylase and non-heme iron-dependent oxygenases, we herein report the first modular, dual catalytic difunctionalization of unactivated alkenes via manganese-catalyzed radical ligand transfer (RLT). This RLT elementary step involves a coordinated nucleophile rebounding to a carbon-centered radical to form a new C-X bond in analogy to the radical rebound step in metalloenzymes. The protocol leverages the synergetic cooperation of both a photocatalyst and earth-abundant manganese complex to deliver two radical species in succession to minimally functionalized alkenes, enabling modular diversification of the radical intermediate by a high-valent manganese species capable of delivering various external nucleophiles. A broad scope (97 examples, including drugs/natural product motifs), mild conditions, and excellent chemoselectivity were shown for a variety of substrates and fluoroalkyl fragments. Mechanistic and kinetics studies provide insights into the radical nature of the dual catalytic transformation and support radical ligand transfer (RLT) as a new strategy to deliver diverse functionality selectively to carbon-centered radicals.


Asunto(s)
Alquenos , Manganeso , Alquenos/química , Carbono , Catálisis , Ligandos , Manganeso/química
15.
Chem Commun (Camb) ; 58(31): 4869-4872, 2022 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-35348566

RESUMEN

C-H Azidation is an increasingly important tool for bioconjugation, materials chemistry, and the synthesis of nitrogen-containing natural products. While several approaches have been developed, these often require exotic and energetic reagents, expensive photocatalysts, or both. Here we report a simple and general C-H azidation reaction using earth-abundant tetra-n-butylammonium decatungstate as a photocatalyst and commercial p-acetamidobenzenesulfonyl azide (p-ABSA) as the azide source. This system can azidate a variety of unactivated C(sp3)-H bonds in moderate to good yields and excellent turnover numbers. Preliminary mechanistic experiments implicate a radical mechanism proceeding VIA photo-hydrogen atom transfer (photo-HAT).


Asunto(s)
Azidas , Hidrógeno , Azidas/química , Catálisis , Hidrógeno/química , Nitrógeno/química
16.
Trends Chem ; 4(12): 1062-1064, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37389032

RESUMEN

Nagib and Rajanbabu share a clever approach to remote desaturation triggered by metal-catalysed hydrogen atom transfer (mHAT) to an alkene, followed by intramolecular 1,6-HAT, and terminated via mHAT. This method both realizes a valuable synthetic transformation and provides multiple lessons for the design of HAT-mediated reactions.

17.
Chem Commun (Camb) ; 57(15): 1871-1874, 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33502408

RESUMEN

Ketones with remote fluorination are an important motif in the synthesis of bioactive molecules. Here we demonstrate that ceric ammonium nitrate (CAN) is able to produce this functionality under incredibly mild conditions and short reaction times (30 min) while eliminating the need for precious metals in previous methods. Importantly, this method allows the efficient synthesis of a wide variety of γ-fluoroketones and is highly scalable. Preliminary mechanistic studies suggest this reaction proceeds through a radical pathway.

18.
Wellcome Open Res ; 6: 150, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35243005

RESUMEN

Background: Music based interventions have been found to improve wellbeing for people with dementia. More recently there has been interest in physiological measures to provide additional information about how music and singing impact this population. Methods: This multiple-case study design explored physiological responses (heart rate-HR, electrodermal activity-EDA, movement, and skin temperature-ST) of nine people with mild-to-moderate using simulation modelling analysis.             Results: In study 1,  the singing group showed an increase in EDA (p < 0.01 for 8/9 participants) and HR (p < 0.01 for 5/9 participants) as the session began. HR (p < 0.0001 for 5/9 participants) and ST (p < 0.0001 for 6/9 participants) increased during faster tempos. EDA (p < 0.01 all), movement (p < 0.01 for 8/9 participants) and engagement were higher during singing compared to a baseline control. In study 2 EDA (p < 0.0001 for 14/18 data points [3 music conditions across 6 participants]) and ST (p < 0.001 for 10/18 data points) increased and in contrast to the responses during singing, HR decreased as the sessions began (p < 0.002 for 9/18 data points). EDA was higher during slower music (p < 0.0001 for 13/18 data points), however this was less consistent in more interactive sessions than the control. There were no consistent changes in HR and movement responses during different music genre.   Conclusions: Physiological measures provide valuable information about the experiences of people with dementia participating in musical activities, particularly for those with verbal communication difficulties. Future research should consider using physiological measures. video-analysis and observational measures to explore further how engagement in specific activities, wellbeing and physiology interact.

19.
J Am Chem Soc ; 142(45): 19316-19326, 2020 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-33119986

RESUMEN

Radical hydrogenation via hydrogen atom transfer (HAT) to alkenes is an increasingly important transformation for the formation of thermodynamic alkane isomers. Current single-catalyst methods require stoichiometric oxidant in addition to hydride (H-) source to function. Here we report a new approach to radical hydrogenation: cooperative hydrogen atom transfer (cHAT), where each hydrogen atom donated to the alkene arrives from a different catalyst. Further, these hydrogen atom (H•) equivalents are generated from complementary hydrogen atom precursors, with each alkane requiring one hydride (H-) and one proton (H+) equivalent and no added oxidants. Preliminary mechanistic study supports this reaction manifold and shows the intersection of metal-catalyzed HAT and thiol radical trapping HAT catalytic cycles to be essential for effective catalysis. Together, this unique catalyst system allows us to reduce a variety of unactivated alkene substrates to their respective alkanes in high yields and diastereoselectivities and introduces a new approach to radical hydrogenation.

20.
Gerontologist ; 60(6): 1115-1125, 2020 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-31812993

RESUMEN

BACKGROUND AND OBJECTIVES: Research has indicated the benefit of music interventions on biological, psychological, and cognitive aspects of dementias, yet there is limited research focusing on music's role in communication. This study developed a conceptual understanding of how people with late-stage dementia may express themselves nonverbally and interact with others during a live music group over time. RESEARCH DESIGN AND METHODS: Eight people with advanced dementias in residential care (aged 82-97 years), four care staff, and three musicians participated in 8-hr-long weekly live Music for Life sessions and listened to 1-hr-long recorded music session. Visual grounded theory was used to analyze video data collected nonintrusively via the Fly 360-degree camera. RESULTS: The live music group facilitated a multisensory communicative environment allowing for verbal and nonverbal communicative actions, social interactional components and agency to develop over time. These aspects were influenced by three factors: time, one-to-one interaction within a group setting and the characteristics of the music. DISCUSSION AND IMPLICATIONS: Nonverbal communication in later-stage dementia may be overlooked or underestimated by busy care staff and families. Using music as an interactive way to communicate can help develop mirroring and turn-taking which has been shown to improve quality of life for people with communication impairment, increase their nonverbal communication and allow for a connection to be built between people. Although further research is recommended, individuals responsible for residential care should feel confident that the development of ongoing music groups for this population is warranted as part of ongoing care.


Asunto(s)
Demencia , Musicoterapia , Música , Anciano de 80 o más Años , Comunicación , Humanos , Calidad de Vida
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