Chemoselective Nucleophilic Fluorination Induced by Selective Solvation of the S_N2 Transition State

Abstract

Reaction of the fluoride ion with secondary alkyl halides leads to 90% of elimination reaction and only 10% of nucleophilic substitution in dipolar aprotic solvents. Adding water to the organic phase, the SN2 yield increases in the cost of decreased reactivity. Using ab initio calculations, we have shown that it is possible to increase the reaction rate and the selectivity toward the SN2 process through supramolecular organocatalysis. The catalytic concept is based on selective solvation of the transition state through two hydrogen bonds provided by the 1,4-benzenedimethanol. The two hydrogen bonds between the catalyst and the SN2 transition state favor this pathway while just one strong hydrogen bond between the catalyst and the fluoride ion leads to a lower stabilization of the nucleophile, resulting in a higher reaction rate. Our calculations predict that the substitution product increases to 40% yield because of the selective catalysis provided by the 1,4-benzenedimethanol.

Palladium‐Catalyzed Allylic Fluorination

“…TBAF·-(tBuOH) 4 (279 mg, 0.5 mmol) was then added in one portion. The reaction was stirred at RT for 1 h. The reaction was quenched by the addition of NH 4 Cl (aq) .…”

“…their very high hygroscopicity. We therefore turned to tetra-nbutylammonium tetra(tert-butyl alcohol)-coordinated fluoride [TBAF·(tBuOH) 4 ; 4]; a reagent that possesses low hygroscopicity and is reported to display good nucleophilicity and low basicity (entries 3-7).…”

“…[12] Pleasingly, we found that fluorination of 1 e with 2.5 equivalents of TBAF·(tBuOH) 4 in the presence of 5 mol % of [Pd(dba) 2 ] and 15 mol % PPh 3 for one hour at room temperature, led to the isolation of the allylic fluoride 2 in quantitative yield (entry 5). A control experiment confirmed that the presence of the catalyst is essential for the fluorination to proceed (entry 6).…”

“…One limitation of the current protocol is a propensity for the competing elimination to give diene products, when possible. For example, reactant 33 gives approximately 5 % of the desired allyl fluoride, as well as the 4 À salt. dba = dibenzylideneacetone, TBAF = tetra-n-butylammonium fluoride, THF = tetrahydrofuran.…”

Organocatalysis: Fundamentals and Comparisons to Metal and Enzyme Catalysis

“…Competition between the S N 2 and E 2 H processes can be affected by temperature, solvent and the amount of water present in the reaction mixture. Although water makes stable clusters F − (H 2 O) n with much less reactivity than naked F − [296] the proportion of S N 2 versus E 2 H product might increase [297,298]. Transition metal-free procedures for the Sonogashira reaction have been performed in water as solvent, polyethyleneglycol (PEG) as a phase-transfer agent, and NaOH as a base (Scheme 42).…”