Nucleophilic fluorination of sulfonyl chlorides, acyl chlorides, and alkyl sulfonates with saturated aqueous solution of potassium bifluoride (KHF2) was studied under liquid–liquid two-phase ...conditions. Original “on-water” procedure, reported by Sharpless et al. ( J. Org. Chem. 2016, 81, 11360−11362, DOI: 10.1021/acs.joc.6b01423 ), was tested on model 1-octanesulfonyl chloride in the presence of phase transfer catalysts, some of which appeared to be beneficial for the reaction rate. Despite the high hydration energy of the fluoride ions, the catalytic system displayed numerous features typical for interfacial transportation of the nucleophilic species, being controlled by amount and structure of the catalyst, lipophilicity of the catalyst’s counterion, and rate of stirring. Besides for synthesis of acyl fluorides presence of 1 mol % of tetrabutylammonium chloride affected the selectivity of the reaction by minimizing formation of carboxylic acids and anhydrides. The presented results suggest that aqueous solutions of bifluorides (or synthetically equivalent systems accessible by acidification of alkali metal fluoride solutions) can be efficient sources of the fluoride ions under two-phase conditions, provided that rate of the intrinsic reaction is sufficiently high. The methodology supplements family of nucleophilic fluorinations, delivering a more reactive form of the solvated anions.
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•Accurate free energy profile including transmetalation step.•Unimolecular elimination of HF leads to regioisomers.•Located critical transition states for further ligand design.
...Palladium catalyzed fluorination of aryl halides with inorganic fluoride salts has been a challenge transformation during several decades. The successful catalysis came with the use of biaryl monophosphine ligand. However, the catalytic process suffers of the problem of off-cycle transformation as ligand modification and formation of regioisomers, which means that more ligand design is necessary. In this work, the complete free energy profile for the catalysis using tBuBrettPhos ligand was determined by reliable theoretical calculations, including the transmetalation step. The calculations have indicated that monocoordination by phosphine and the bulky groups in the tBuBrettPhos ligand, which has strong repulsion to the coordinating bromide ion, are critical to achieve low activation barriers for reductive elimination. The ligand modification transition state was found and involves migration of the coordinating aryl group. The mechanism of regioisomers formation, an important drawback of this methodology, was also found and corresponds to the elimination of HF without participation of CsF, forming a benzyne intermediate coordinating to the palladium. The return of the HF can take place by proton donation to any carbon of the benzyne, which produces the isomerization. These findings indicate that more rational ligand design can be done to produce more effective catalysis. The theoretically determined rate law and the overall ΔG‡ are in excellent agreement with experimental data.
Nucleophilic fluorination via copper catalysis has been a challenging transformation and only special substrates can react. One example is the 2-(2-bromophenyl)pyridine, which was fluorinated with ...AgF using CuPF6 catalyst in acetonitrile solvent. In this work, a detailed analysis of this catalyzed reaction was done using theoretical methods. The free Cu+ ion and the CuF ion pair in acetonitrile solvent were modeled using a quasi-chemical cluster-continuum approach and electronic energies calculated at DLPNO-CCSD(T) level with a quadruple-zeta basis set. The catalytic cycle involves the Cu(I)/Cu(III) mechanism via cationic (Cu+ ion) or neutral (CuF ion pair) pathways. The solubility of AgF and CuF was included in the analysis, as well as the transmetalation step. The calculated free energy profile was used to perform a microkinetic analysis of the reaction system. The results point out that the reaction proceeds via the cationic mechanism, with the formation of the catalyst-substrate complex followed by the oxidative addition step with ΔG‡ = 30.8 kcal mol−1. The formed intermediate is high in free energy and the reductive elimination step is the rate-determining one, with an overall ΔG‡ = 32.6 kcal mol−1. Analysis of the free energy profile and the microkinetic modeling point out almost zero-order kinetics in substrate concentration when the catalyst is used in substoichiometric quantity. Approximated experimental ΔG‡ is estimated as being 30.7 kcal mol−1, in very good agreement with the theoretical value. The neutral mechanism with the soluble CuF ion pair has ΔG‡ = 33.4 kcal mol−1, which is competitive with the cationic mechanism. However, due to the low solubility and concentration of this ion pair, the reaction does not take place by this pathway.
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Bulk alcohols like tert-butanol have been investigated as reaction medium for SN2 reactions, especially nucleophilic fluorination. Nevertheless, details of alkali metal salts in tert-butanol ...solution, as well as the transition state solvation, have not been investigated. This work presents a molecular dynamics study of pure tert-butanol and solution of KF in tert-butanol. The interaction and structure of the SN2 transition state in tert-butanol solution has also been investigated using both molecular dynamics and density functional theory calculations. In the last case, the transition state is solvated by a cluster of four tert-butanol molecules and by a dielectric continuum. The present study point out the KF and CsF salts form ion pairs in tert-butanol, and the strong interaction of hydroxyl groups of tert-butanol with both cation and anion, combined with low entropy for formation of cluster in solution, facilitates the solubilization of inorganic salts, although the solubility is predicted be low. The reaction of solubilized KF and CsF has low free energy of activation and the transition states involve participation of the tert-butanol molecules. This fact turns the CsF more reactive than KF. The free energy of activation for CsF reaction with ethyl bromide is predicted to be 28.4kcalmol−1, close to the experimental value of 28.9kcalmol−1 for a similar system.
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•tert-Butanol molecules form cyclic clusters in liquid phase.•KF and CsF form ion pairs in solution and have strong interaction with hydroxyl groups of tert-butanol.•tert-Butanol molecules participate of the SN2 transition state and favor CsF reaction in relation to KF.
Nucleophilic ionic sources of fluoride are essential reagents in the synthetic toolbox to access high added-value fluorinated building blocks unattainable by other means. In this review, we provide a ...concise description and rationale of the outstanding features of one of these reagents, tetramethylammonium fluoride (TMAF), as well as disclosing the different methods for its preparation, and how its physicochemical properties and solvation effects in different solvents are intimately associated with its reactivity. Furthermore, herein we also comprehensively describe its historic and recent utilization, up to December 2021, in C-F bond-forming reactions with special emphasis on nucleophilic aromatic substitution fluorinations with a potential sustainable application in industrial settings, as well as its use as a base capable of rendering unprecedented transformations.
Herein, we present an efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates. Each step of the synthesis was optimized to provide excellent yields. Moreover, the absolute ...configuration of the obtained compounds was determined by X-ray analysis, which proved the stereochemistry that was proposed based on NMR studies.
The PET tracer 18FF‐AraG, an arabinosyl guanine analog, has shown promise for visualizing activated T cells in multiple diseases. Herein, a practitioner's protocol is described, in which the PET ...tracer is prepared using minimal equipment and manual actions, making it widely accessible for preclinical applications.
Theoretical calculations were performed to elucidate the ability of the recently reported bis‐tert‐alcohol‐functionalized crown‐6‐calix4arene (BACCA) molecule to promote nucleophilic fluorination of ...alkyl mesylates with cesium fluoride reagent. It was found that a similar structure, named BACCAt, can separate the cesium fluoride ion pair in tert‐butanol solution. This separation has a free energy cost, even considering the double hydrogen bonds with the fluoride ion. The solvent has an important effect on the stabilization of this complex, due to interaction with the high dipole moment of the separated ion pair. The observed rate acceleration effect involves a structure with double hydrogen bonds between the BACCAt and the centers of negative charges of the SN2 transition state. The predicted free energy barrier of 27.3 kcal mol−1 is in excellent agreement with the estimated experimental value of 26.2 kcal mol−1.
Use of alkaline fluorides as fluorine source in chemical reactions is a challenge due to required solubilization and activation of the MF salt. Theoretical calculations show that a bis‐tert‐alcohol‐functionalized crown‐6‐calix4arene can promote nucleophilic fluorination via solubilization of CsF salt, separation of the ion pair and double hydrogen bonds to the centers of charge of the SN2 transition state.
Syntheses of salts of perfluoroalkyltrifluoroborate anions RFBF3−starting from perfluoroalkyltrimethoxyborates, potassium bifluoride, and mineral or organic acids have been developed. These reactions ...avoid the use of highly toxic and corrosive anhydrous hydrogen fluoride.
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Perfluoroalkyltrimethoxyborates were converted into the corresponding perfluoroalkyltrifluoroborates in high yield by the action of potassium bifluoride in acidic media, i.e. in hydrochloric acid (37%), glacial acetic acid, and trifluoroacetic acid as well as in acidic ionic liquids. These low-cost methods avoid the use of toxic and corrosive hydrofluoric acid or anhydrous HF (aHF). Potassium and sodium perfluoroalkyltrifluoroborates are highly valuable starting materials for the preparation of low viscosity ionic liquids and organic salts with RFBF3− anions, in general, and for the synthesis of further perfluoroalkylborate anions, for example perfluoroalkylcyanofluoroborates RFBF3-n(CN)n− (n = 1–3). Furthermore, complex metal cations are accessible with the weakly coordinating RFBF3− counterions, as exemplified by the synthesis of Cu(bpy)3C2F5BF3 (bpy = 2,2′-bipyridine).
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► The central K+ cation favors SN2 over E2 anti. ► The crown ring favors SN2 over E2 syn. ► The released KBr inhibits the catalysis.
Crown ethers have the ability of solubilizing ...inorganic salts in apolar solvents and to promote chemical reactions by phase-transfer catalysis. However, details on how crown ethers catalyze ionic SN2 reactions and control selectivity are not well understood. In this work, we have used high level theoretical calculations to shed light on the details of phase-transfer catalysis mechanism of KF reaction with alkyl halides promoted by 18-crown-6. A complete analysis of the of the model reaction between KF(18-crown-6) and ethyl bromide reveals that the calculations can accurately predict the product ratio and the overall kinetics. Our results point out the importance of the K+ ion and of the crown ether ring in determining product selectivity. While the K+ ion favors the SN2 over the E2 anti pathway, the crown ether ring favors the SN2 over E2 syn route. The combination effects lead to a predicted 94% for the SN2 pathway in excellent agreement with the experimental value of 92%. A detailed analysis of the overall mechanism of the reaction under phase-transfer conditions also reveals that the KBr product generated in the nucleophilic fluorination acts as an inhibitor of the 18-crown-6 catalyst and it is responsible for the observed slow reaction rate.
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