In a heterogenous system, in the presence of phase-transfer catalyst, unassociated halide ions can be obtained. In these systems, anionic reagents continuously transfer from an aqueous to an organic phase by means of organic cations. Anions would be reactive, in the case of the poor solvation and low energy of interaction with the cation. In 1974, Montanari et al.82 reported displacement of primary or secondary alkyl chloride and alkyl bromides by fluorine under vigorously stirring at 100-160 °C with a saturated aqueous solution of potassium fluoride and catalytic amounts of hexadecyltributylphosphonium bromide. Reaction of 1-chloroalkane in presence of 5 mol of potassium fluoride at 160 °C in 6-8 h afforded alkyl fluorides in 80% yield and olefins as well as primary alcohols as a by- products. The same results were obtained by using 1.5 mol potassium fluoride with longer reaction times, approximately 16 h. When reaction was conducted at lower temperatures
59 (110-120 °C) after 8-10 h only 25-30% conversion was happened, even the use of an excess of potassium fluoride did not change the percentage of conversion. However, benzyl chloride was converted to the corresponding fluoride at 120 °C after 7 h in high yield. The conversion of secondary halo derivatives was noticeably slower, and elimination products predominated over substitution products. The ratio of elimination products to substitution products increased as the temperature was elevated. In 1984, Cox et al.83 reacted anhydrous tetrabutylammonium fluoride (TBAF) with a halo- or tosyl- substituted organic compounds such as allylic, benzylic, primary, secondary, and tertiary which afforded corresponding fluoro compounds with 48-98% yield. Significantly, these reactions were conducted at low temperatures between 25-40 °C and short reaction times of 0.1 to 8 h. In the case of 2- bromooctane and 2-octyl tosylate, elimination of HBr and TsOH predominated rather than fluorination due to the fact that anhydrous TBAF can behave as a potent base rather than as a nucleophile. However, hydrolysis of the substrate halide or tosylate, such as benzyl bromide, chlorotriphenylmethane, or 1-bromooctane, to the corresponding alcohol was a significant side reaction. The alcohol products likely were formed by the remaining traces of moisture in the reagent. Moreover, the reaction of anhydrous TBAF with (-)-2-octyltosylate yielded (+)- 2-fluorooctane in good yield and 100% optical purity. Based on the comparison of the value and sign of the specific rotation of resulting (+)-2-fluorooctane with the previously reported,84 the discussed fluorination reaction proceeds via an SN2 mechanism. In this
context, and considering the higher leaving group ability of triflates compare to halides, mesylates, or tosylates, Shin et al. 85 investigated the reactivity of triflates in presence of fluoride ion species which are less nucleophilic compared to TBAF. As such, the basicity of fluoride would be reduced and the formation of the elimination side product would be
60 minimized. Therefore, the reaction of triflate 142 (figure 21) with tetrabutylammonium fluoride (TBAF), bifluoride (TBABF), dihydrogen-trifluoride (TBADTF), and hydrogen fluoride pyridine complex, which are less nucleophilic and less basic in character, were tested. The best result was obtained by using an in situ formed solution of triflate 142 in dichloromethane with TBABF. Formation of the elimination product under these conditions was only 3%, while the use of TBAF gave 28% elimination product in the same reaction condition. The same level of elimination product formed using less basic dihydrogen trifluoride, however, high quantity of unidentified by-product yielded. With the least basic hydrogen fluoride pyridine complex, only decomposition of 142 was obtained. In addition, a
Figure 21. Stucture of proline 142.
number of primary alcohols such as 143 were tested under the condition shown in Scheme 37, to afford the fluorinated products of 145 through intermediates 144 with up to 92% yield in 1h. For secondary acyclic alcohols, the elimination reaction was happened in the range of between 7 to 46%. In addition, having ester or lactone group at α position to hydroxyl groups gave excellent yields.85
61 Scheme 37. Nucleophilic fluorination of triflates substrates.
A new type of phase-transfer catalysis was introduced by Makosza el al. 86 in which fluoride anions transfer to the organic phase in the form of potassium difluorotinorgano- stannate. Initially, in these reactions triorganotin fluorides in presence of solid KF form hypervalent difluorotinorganostannate anions. Subsequently, ion exchange with tetraalkylammonium (TAA) salts Q+X– produce liphophilic ion-pairs of the difluorotinorganostannate with TAA cations. These ion-pairs transfer to organic phase and react with R‒X to afford R‒F and triorganotin fluoride. Reaction of resulting triorganotin fluoride with KF reproduces difluorotinorganostannate to participate in another reaction sequence (Scheme 38). Notably, they found that fluorination of alkyl halides in sulfolane
Scheme 38. Fluorination of alkyl halide using hypervalent difluorotriorganostannate.
proceeded without Q+X– , it means that R3SnX promoted the reaction by itself. As a result,
hypervalent anion R3SnF‒2K+ should be sufficiently soluble in the solvent to react with R–X.
Accordingly, they presented new concept of PTC in which complexation of reacting anion with appropriate catalyst produce lipophilic anions. The solubility of the potassium salts of these liphphilic anions are sufficient for transferring to the organic phase. The reaction of the
62 complexed anion in organic phase liberates catalyst, which in turn forms a new complexed anion (Scheme 39). Makosza el al. tested triphenyltin fluoride for fluorination of benzyl
Scheme 39. Fluorination of alkyl halide using potassium difluorotriarylstannate.
bromide in different solvent systems and it was found that sulfolane and DMF gave 54% while acetonitrile afforded only 3% yield. As it is shown in Table 3 alkyl –mesylates, – tosylate, and -halide gave fluorination products with 70-100% yield determined by GLC.86
63 Table 3. Fluorination of alkyl -mesylates and –tosylate with triphenyltin fluoride in different solvent systems. R–X Solvent Temperature (°C) Time (h) Yielda (%) of R–F PhCH2Br Mixb 95 24 100 PhCOCH2Br Sulf 85 4 92 PhCOCH2Br Mix 95 4 70 n-C8H17OMs Sulfc 105 24 90 2-C8H17OTs Sulf 85 48 80
4-NO2Ph(OMs)CHCH3 Mix 95 8 85
a Yield determined by GLC. b Mix-sulfolane+acetonitrile, 1:2. c Sulfolane.