A Frustrated Lewis Pair Solution to a Frustrating Problem: Mono-Selective Functionalization of C–F Bonds in Di- and Trifluoromethyl Groups

Gupta, Richa; Jaiswal, Amit K.; Mandal, Dipendu; Young, Rowan D.

doi:10.1055/s-0039-1690811

Cited by 30 publications

(9 citation statements)

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“…[13] In contrast, the resulting phosphonium or pyridinium salts formed in this novel FLP-mediated process are "deactivated" intermediates that can be furtherf unctionalized by nucleophilic substitutions or electrophilic transfer reactions,t herefore leading to aw ide variety of products with potential applications in medicinal chemistry or materials science. [9][10][11] Despite the evident syntheticp otentialo ft his transformation, which can be even performed catalytically in the Lewis acid by the additiono fT MSNTf 2 as af luorides equestering agent, [10,14] very little is knowna bout the actual role of the FLP in the process. For this reason,w ed ecided to gain ad etailed understanding of the unknown cooperative action of the FLP partnersi nt he transformation.…”

Section: Introductionmentioning

confidence: 99%

“…In this regard, FLPs were recently applied by Young and co‐workers to activate a single C−F bond in di‐ and trifluoromethyl groups (Scheme 1). [9–11, 12] The use of FLPs in this reaction constitutes an elegant solution to the longstanding problem of multiple C−F functionalizations typically observed in Lewis acid‐catalyzed reactions, which derives from the lower reactivity of the polyfluoride starting materials with respect to their substituted products [13] . In contrast, the resulting phosphonium or pyridinium salts formed in this novel FLP‐mediated process are “deactivated” intermediates that can be further functionalized by nucleophilic substitutions or electrophilic transfer reactions, therefore leading to a wide variety of products with potential applications in medicinal chemistry or materials science [9–11] …”

Section: Introductionmentioning

confidence: 99%

“… Mono‐selective functionalization of C−F bonds in di‐ and trifluoromethyl groups described by Young and co‐workers (see refs. [9]–[11]). …”

Section: Introductionmentioning

confidence: 99%

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Understanding the C−F Bond Activation Mediated by Frustrated Lewis Pairs: Crucial Role of Non‐covalent Interactions

Cabrera-Trujillo

Fernández

2021

Chemistry A European J

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The activation of a single C−F bond in di‐ and trifluoromethyl groups by frustrated Lewis pairs (FLPs) has been computationally explored by means of Density Functional Theory calculations. It is found that in this activation reaction the FLP partners exhibit a peculiar cooperative action, which is markedly different from related FLP‐mediated processes, and where non‐covalent interactions established between the Lewis base and the substrate play a decisive role. In addition, the process proceeds through the intermediacy of a hypervalent species featuring a pentacoordinate carbon atom, which is rare in the chemistry of FLPs. The physical factors controlling this process as well as the bonding situation of these hypervalent intermediates have been quantitatively analyzed in detail by using state‐of‐the‐art computational methods to not only rationalize the mechanism of the transformation but also to guide experimentalists towards the realization of these so far elusive hypervalent systems.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Understanding the C−F Bond Activation Mediated by Frustrated Lewis Pairs: Crucial Role of Non‐covalent Interactions

Cabrera-Trujillo

Fernández

2021

Chemistry A European J

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“…Given the much lower barrier for C–F activation via an AlCl 3 -mediated S N 1 mechanism, we then investigated the possibilities for halide delivery to the intermediate carbocation (Figure ). We have reported on selective C–F activation, where a Lewis base reacts directly with an intermediate carbocation . The analogous reaction in halodefluorination involves direct attack of the intermediate carbocation by TMSCl with a kinetic barrier of 15.9 kcal mol –1 (the barrier without [AlCl 3 F] − is 18.3 kcal mol –1 , see Figure S3).…”

Section: Results and Discussionmentioning

confidence: 99%

Insights into the Mechanism of Aluminum-Catalyzed Halodefluorination

et al. 2023

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Aluminum has been reported to catalyze halodefluorination reactions, where aliphatic fluorine is substituted with a heavier halogen. Although it is known that stoichiometric aluminum halide can perform this reaction, the role of catalytic aluminum halide and organyl alane reagents is not well understood. We investigate the mechanism of the halodefluorination reaction using catalytic aluminum halide and stoichiometric trimethylsilyl halide. We explore the use of B(C 6 F 5 ) 3 as a catalyst to benchmark pathways where aluminum acts either as a Lewis acid catalyst in cooperation with trimethylsilyl halide or as an independent halodefluorination reagent which is subsequently regenerated by trimethylsilyl halide. Computational and experimental results indicate that aluminum acts as an independent halodefluorination reagent and that reactivity trends observed between different halide reagents can be attributed to relative barriers in halide delivery to the organic fragment, which is the rate-limiting step in both the aluminum halide-and B(C 6 F 5 ) 3catalyzed pathways.

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“…We have reported on the nucleophilic substitution of TPPy by halides for synthetic purposes in high yields, [8b–d] however, the extremely low concentration of fluorine‐18 used in generating PET radiotracers can often result in marked differences between observed chemical and radiochemical yields. As such, optimization of the radioactive fluorination reaction was performed using 2 a (Table 1).…”

Section: Figurementioning

confidence: 99%

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

et al. 2022

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We report a general method for the labeling of both CF 3 and CF 2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective CÀ F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2 � 6.5 % non-decay corrected isolated activity yields and 12.0 � 1.7 GBq μmol À 1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF 3 and CF 2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development.In molecular imaging, fluorine-18 (t 1/2 � 110 min) finds use as the most suitable radionuclide for positron-emission tomography (PET). [1] PET utilizes radiotracers that contain (most commonly) the positron-emitting fluorine-18 to noninvasively image biological tissue and organs in real-time. Most notably, PET is utilized in diagnostic medicine but has also found application in pharmacokinetic studies. [2] Recent attention has turned to the incorporation of fluorine-18 into difluoromethyl and trifluoromethyl groups due to their increasing presence in bioactive molecules as bioisosteres. [3] The ability to readily label CF 3 and CF 2 H groups with fluorine-18 in biologically relevant molecules for use in PET would directly benefit drug development, pharmacokinetic studies and biological imaging. [4] A number of reports have demonstrated incorporation of fluorine-18 into CF 2 H and CF 3 (Figure 1, A). [5] For example, halogen exchange (Halex) has been utilized to generate fluorine-18 labeled CF 2 H and CF 3 groups, most successfully with bromide leaving groups. [5a-k] The harsh reaction conditions required for exchange of CÀ X bonds

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A Frustrated Lewis Pair Solution to a Frustrating Problem: Mono-Selective Functionalization of C–F Bonds in Di- and Trifluoromethyl Groups

Cited by 30 publications

References 4 publications

Understanding the C−F Bond Activation Mediated by Frustrated Lewis Pairs: Crucial Role of Non‐covalent Interactions

Understanding the C−F Bond Activation Mediated by Frustrated Lewis Pairs: Crucial Role of Non‐covalent Interactions

Insights into the Mechanism of Aluminum-Catalyzed Halodefluorination

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

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