Wissenschaft + Forschung

PD Dr.

Die Milner-Gruppe an der Cornell-Universität macht gasförmige Organofluorverbindungen wie Vinylidendifluorid (1), Trifluorpropen, Hexafluorpropen oder Trifluoriodmethan praktisch anwendbar, indem sie diese in metallorganische Gerüste einlagert. So nehmen 120 mg des Mg2(dobdc)-Gerüsts 1 mmol (1) auf; Verkapselung in Wachs führt zu lagerstabilen Einschlussverbindungen. Die Konstrukte (2) eignen sich für palladiumkatalysierte Kreuzkupplungen mit Arylboronsäuren; sie liefern α-Fluorstyrole (3) in Ausbeuten, die mehr als 20 % höher sind als die von frisch im metallorganischen Gerüst adsorbiertem (1). Negishi- oder Heck-Reaktionen mit ähnlich präparierten Einschlussverbindungen sowie Radikaladditionen mit Trifluormethyliodid sind ebenfalls leicht und in guten Ausbeuten durchführbar. UJ<img alt="image" src="https://media.graphassets.com/7lZOOEKfS5e901TOqaJi"><ul class="references" style="numbered" xml:id="nadc20234136127-bibl-0014" cited="no"><li xml:id="nadc20234136127-bib-0014">Science 2023, 381, 1455</li></ul>

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Eingesperrte gasförmige fluororganische Reagenzien

Die Milner-Gruppe an der Cornell-Universität macht gasförmige Organofluorverbindungen wie Vinylidendifluorid (1), Trifluorpropen, Hexafluorpropen oder Trifluoriodmethan praktisch anwendbar, indem sie diese in metallorganische Gerüste einlagert. So nehmen 120 mg des Mg2(dobdc)-Gerüsts 1 mmol (1) a...

Blickpunkt Synthese

Today, alcohols as building blocks for synthesis go beyond ether and ester formation. Photochemistry and electrochemistry activate the carbon-oxygen bond to form carbon-carbon bonds and carbon-boron bonds for cross-coupling reactions.Alcohols are the most common commercially available alkyl fragment (<link href="#nadc20234134060-fig-0001">Figure 1, top left). Therefore, methods to activate the C–O bond would benefit both industry and academia by providing a vast library of alkyl coupling partners. However, the reactivity of hydroxy groups has classically been limited to nucleophilic attack of various electrophilic moieties by the O atom, for instance esterification and SN2 type reactivity.<figure xml:id="nadc20234134060-fig-0001"><figure><img alt="image" src="https://media.graphassets.com/Im25cJRQG47DHr1sVGAO"><figcaption><label>Abb.1: </label>Bar chart showing the relative commercial availability of various alkyl synthons (top left); a comparison between bond dissociation energies of C–O and C–Br bonds (top right); the Chugaev elimination and Barton-MacCombie reaction (bottom).</figcaption></figure></figure><h2 type="main">Thermodynamic barriers</h2>Indeed, part of the reason why the C–O bonds of alcohols are rarely cleaved is a high bond dissociation energy (BDE). Cleaving the hydroxyl C–O bond requires at least 20 kcal mol–1 more energy than dissociating its bromide counterparts (Figure 1, top right), which are often exploited in organic transformations.<h2 type="main">Cleaving the carbon-oxygen bond</h2>The first examples of C–O bond cleavage are traced back to the Chugaev elimination of an alcohol to an olefin in the late 19th century (Figure 1, bottom).1) In the mid-1970s, Barton and McCombie reported a tin radical-mediated alcohol deoxygenation to form a carbon-centered radical. Scavenging a hydrogen radical from tributyltin hydride forms an alkene – a method that has inspired more recent developments.2) For instance, in the early 2000s, John Wood and co-workers reported a variation that used water as a source of hydrogen.3) A modified tin-free, visible light photocatalyzed modification was reported by Cyril Ollivier and co-workers.4) Other deoxygenation strategies relying on phosphite and phosphoranyl radicals have been reported by the Koreeda,5) and Doyle and Rovis6) groups. However, most of the aforementioned methods require the hydroxy moiety to be derivatised beforehand and form alkanes and alkenes.Methods to form carbon-carbon or carbon-heteroatom bonds developed more recently.<h2 type="main">Carbon-carbon bonds</h2>MacMillan and co-workers have recently demonstrated C–C cross-coupling reactions where the alcoholic C–O bonds are activated by a combination of a metallophotoredox process and N-heterocyclic carbene (NHC) activation (<link href="#nadc20234134060-fig-0002">Figure 2). In these reactions, the NHC activates the alcohols in-situ. The resulting product upon reaction with the NHC undergoes Single Electron Transfer (SET) oxidation with a photocatalyst. This is followed by fragmentation to form an alkyl radical driven by formation of a new carbonyl bond. This alkyl radical can now either be trapped by an aryl nickel(II) complex to form a new C(sp3)-C(sp2) bond or alternatively a new C(sp3)-C(sp3) bond can be formed.7) This occurs via a nickel mediated SH2 radical sorting process whereby the less sterically hindered radical is captured by the metal centre and undergoes homolytic substitution.8)<figure xml:id="nadc20234134060-fig-0002"><figure><img alt="image" src="https://media.graphassets.com/u7dOTjRXT1228QDaksZ2"><figcaption><label>Abb.2: </label>MacMillan’s NHC mediated C–O bond activation: C(sp3)-C(sp2) bond formation methodology (top left); C(sp3)-C(sp3) bond formation methodology via radical sorting (top right); mechanisms for the above methodologies (bottom).</figcaption></figure></figure>Another strategy for C–O bond activation relies on Brønsted or Lewis acid catalysis. Since 2020, several examples of titanium-catalysed carbon radical formation from alcohols have been reported (<link href="#nadc20234134060-fig-0003">Figure 3). A group of researchers led by Xing-Zhong Shu discovered that tertiary alcohols can form a carbon-carbon bond with electron-deficient alkenes in a dehydroxylative Giese-type reaction.9) The tertiary alcohols form a complex with Cp*TiCl2 and undergo an intramolecular SET affording a carbon-centered radical (Figure 3, top, p. 54). This reacts with an electron-deficient alkene, giving rise to a C–C bond. The same group later extended this reactivity with vinyl bromides to form a C(sp3)–C(sp2) bond.10) In 2022, Ukaji and co-workers identified a TiCl2(cat)/Zn (cat = catecholate) based system which also forms carbon-centered radicals from alcohols.11) This catalytic platform expanded titanium-based C-O activation reactions to allow generation of radicals from benzylic, primary and secondary alcohols.<figure xml:id="nadc20234134060-fig-0003"><figure><img alt="image" src="https://media.graphassets.com/EIxVP7t5RDGlF5ybPBqV"><figcaption><label>Abb.3: </label>Titanium-catalysed C–O activation: Shu’s activation of tertiary alcohols (top); Ukaji’s method for benzylic, primary, secondary and tertiary alcoholic C–O activation (bottom).</figcaption></figure></figure><h2 type="main">Carbon-boron bonds</h2>Among C–O bond activation towards carbon-heteroatom bond formation, the construction of a C–B bond bond occupies a unique place. This is because the boron group is exploited in transformations like the Suzuki coupling reaction or Zweifel olefination. In 2019, Studer and his team reported two approaches for radical borylation of secondary and tertiary alcohols (<link href="#nadc20234134060-fig-0004">Figure 4, top left, p. 54).12) One involves a metal-free, silane radical-based pathway, while the other one is a visible light-promoted photocatalysed reaction. In the same year, Aggarwal and co-workers reported a photocatalysed Barton-McCombie type radical deoxygenative borylation, which transforms aliphatic alcohols into boronic esters (Figure 4, top right).13) Although these methods open up new reactivities, they still require the alcohols to be pre-functionalised. An approach by Xia et al. circumvents this problem: a boryl radical is generated upon interaction with a photocatalyst (Figure 4, right). Subsequently, a hydroxy group attacks the boryl radical which fragments the OH group and generates a carbon-centered radical (Figure 4, left).14) This radical can be further reduced to yield a carbanion via radical polar crossover.<figure xml:id="nadc20234134060-fig-0004"><figure><img alt="image" src="https://media.graphassets.com/vBzDJnlCRzCAHsT93PwU"><figcaption><label>Abb.4: </label>Recent developments in C–B bond formation by alcohol C–O bond activation – Studer’s methods (top left); Aggarwal’s method (top right); Xia’s and Lin’s methodology (left), corresponding mechanisms (right); examples from Lin’s substrate scope (bottom).</figcaption></figure></figure><h2 type="main">Electrochemical reduction</h2>Under electrocatalytic conditions alcoholic C–O bonds are difficult to homolytically cleave, having a reduction potential of –3.0 V vs. Fc/Fc+ in THF.15) In 2023, Song Lin and his team reported a similar approach to that of Studer. The group used pinacol borane (HBpin) as a reactant as well as an in-situ alcohol activator. During this reaction the alcohol (ROH) first reacts with HBpin to form ROBpin which makes the reduction potential less negative at –2.5 V vs. Fc/Fc+ (Figure 4, right). Now, homolytic C–O bond cleavage eliminates OBpin, leading to a carbon-centered radical. The radical undergoes a radical polar crossover at the cathode to form a carbanion. Since the reaction medium contains HBpin, this carbanion attacks the pinacol borane which forms a new carbon–boron bond. The group drew inspiration for this work from their previous experience with cross-electrophile coupling of tertiary alkyl bromides with primary alkyl bromides which used the same key steps to generate carbanions.16)To synthesise the boronic acid pinacol esters from alcohols, the conditions were optimised: 2.5 equivalents of HBpin, a sacrificial Mg cathode, graphite cathode, tetrabutylammonium tetrafluoroborate (TBABF4) as an electrolyte, and THF as the solvent in an undivided cell. The method extends to aldehydes and ketones as they undergo hydroboration with HBpin leading, in-situ, to the same ROBpin-type intermediate.While being limited to benzylic and allylic alcohols, the methodology converts primary, secondary, and tertiary alcohols, strained ring systems, heterocyclic substrates and macrocyclic alcohols to boronic esters (Figure 4, bottom). Moreover, benzylic alcohols are selectively converted in presence of unactivated hydroxy groups. To convert allylic alcohols, the conditions were modified, i.e. using lithium triflate (LiOTf) as the electrolyte in place of TBABF4.Finally, the authors deoxoborylated several natural products and biologically active molecules such as the alcohol precursors of cholesterol medication rosuvastatin, skin medication podophyllotoxin and Alzheimer’s drug donepezil.<h2 type="main">AUF EINEN BLICK</h2>Reaktionen aktivieren die C–O-Bindungen in Alkoholen hauptsächlich so, dass sie als Alkylfragmente dienen.Die meisten Reaktionen der letzten 20 Jahre derivatisieren die Hydroxygruppen zunächst. Moderne Techniken dagegen aktivieren die wenig reaktive C–O-Bindung in situ.Um das zu erreichen, nutzen sie N-heterocyclische Carbene und Photokatalysatoren sowie Elektrokatalyse mit Borylradikalen.Die Beiträge zur Serie Synthese im Blickpunkt verfassen seit März 2023 im Wechsel Christopher Teskey und Nadja Simeth.<h2 type="main">Die Autoren</h2>Samikshan Jana (top) is a doctoral researcher focused on discovering new methods in radical chemistry. He works at the Institute of Organic Chemistry, RWTH Aachen University in the group of Christopher Teskey (bottom) – a Junior Group Leader at the institute since 2019. Teskey studied Natural Sciences in Cambridge and finished his PhD in 2016 at the University of Manchester. The research interests of the Teskey group centre around the merger of metal catalysis and photochemistry.<img alt="image" src="https://media.graphassets.com/yjxvIYswR2xOm7QPFaiR"><img alt="image" src="https://media.graphassets.com/8hDDILTlRXOBlSFvjZ1i"><ul class="references" cited="no" xml:id="nadc20234134060-bibl-0001" style="numbered"><li xml:id="nadc20234134060-bib-0001">1 Berichte der deutschen chemischen Gesellschaft. 1900, 33(3), 3118–3126</li><li xml:id="nadc20234134060-bib-0002">2 J. Chem. Soc, Perkin Trans. 1975, 16(16), 1574–1585</li><li xml:id="nadc20234134060-bib-0003">3 J. Am. Chem. Soc. 2005, 127, 12513−12515</li><li xml:id="nadc20234134060-bib-0004">4 Adv. Synth. Catal. 2014, 356, 2756−2762.</li><li xml:id="nadc20234134060-bib-0005">5 J. Am. Chem. Soc. 2004, 126, 13190−13191</li><li xml:id="nadc20234134060-bib-0006">6 ACS Catal. 2018, 8, 11134−11139</li><li xml:id="nadc20234134060-bib-0007">7 Nature 2021, 598, 451–456</li><li xml:id="nadc20234134060-bib-0008">8 J. Am. Chem. Soc. 2022, 144, 6185−6192</li><li xml:id="nadc20234134060-bib-0009">9 J. Am. Chem. Soc. 2020, 142, 16787−16794</li><li xml:id="nadc20234134060-bib-0010">10 ACS Catal. 2022, 12(2), 1018–1023</li><li xml:id="nadc20234134060-bib-0011">11 Angew. Chem. Int. Ed. 2022, 61, e2021125</li><li xml:id="nadc20234134060-bib-0012">12 Angew. Chem. Int. Ed. 2019, 58, 9561−9564</li><li xml:id="nadc20234134060-bib-0013">13 Angew. Chem. Int. Ed. 2019, 58, 18830−18834</li><li xml:id="nadc20234134060-bib-0014">14 J. Am. Chem. Soc. 2022, 144, 8551−8559.</li><li xml:id="nadc20234134060-bib-0015">15 J. Am. Chem. Soc. 2023, 145(31) 16966–16972</li><li xml:id="nadc20234134060-bib-0016">16 Nature 2022, 604, 292–297</li></ul>

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Eingesperrte gasförmige fluororganische Reagenzien

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