N-Fluoropyridinium Salts

Lucjan Strekowski; Alexander S. Kiselyov    Department of Chemistry, Georgia State University, Atlanta, Georgia

I Introduction

The reaction of pyridine with molecular fluorine to give 2-fluoropyridine in low yield was first observed by Simons (50MI1). Historically, it was Meinert (65ZC64) who for the first time isolated an intermediate fluorine–pyridine adduct by bubbling elemental fluorine through a solution of pyridine (Py) in CFCl3 at − 80 °C. The white precipitate of apparent structure [PyF]+ F− decomposed violently upon heating to − 2 °C to give a red-brown oil containing 2-fluoropyridine (83IZV2655). The suggested formation of an unstable N-fluoropyridinium cation [PyF]+ was in sharp contrast to the well-known generation of a molecular complex or a stable dicoordinated halogen cation [Py2X]+ by the reaction of chlorine, bromine, or iodine with pyridine (57PCS250; 73MI1; 90JOC3104). The apparently different reactivity of fluorine was discussed in terms of the highest electronegativity of the fluorine atom, its high oxidation potential, low polarizability, the lack of d-orbitals, and extremely poor two-coordinating ability (74MI1; 83MI1). The N-fluoropyridinium cation was not characterized for the next two decades until Umemoto and Tomita (86TL3271) obtained stable N-fluoropyridinium salts. Their report resulted in a renewed interest in the chemistry of the N-fluoropyridinium cation. A substantial volume of primary chemical literature has appeared through February 1994 to warrant this first review.

II Synthesis

It was reasoned that the instability of the fluorine–pyridine complex of apparent structure 1a is due to the high nucleophilicity and/or basicity of the fluoride anion toward the N-fluoropyridinium cation (86TL3271). This assumption proved to be correct, and a large number of stable salts, all of which contained a relatively nonnucleophilic and nonbasic counteranion, were prepared. Selected examples (1–6) (86TL3271; 89JOC1726; 90OS129; 93T2151) and internal salts (7, 8) (90JA8563) are shown.

Most conveniently, pyridinium salts (1–6) are prepared by bubbling elemental fluorine through a solution of the corresponding pyridine and an inorganic salt, such as CF3SO3Na, LiBF4, NaPF6, NaSbF6, or LiClO4, in dry acetonitrile at low temperature. Workup includes filtration of inorganic materials, concentration, and crystallization of 1–6 from acetonitrile. Modified procedures involve generation of a pyridinium fluoride (1a–6a) followed by treatment with the inorganic salt or treatment with BF3 • Et2O in the preparation of a tetrafluoroborate salt. A triflate salt (1b–6b) can also be prepared directly by the reaction of an N-(trimethylsilyl)pyridinium triflate with elemental fluorine in acetonitrile at − 40 °C (86TL3271). Although all these procedures involve work with fluorine, a highly toxic gas and a strong oxidant, the preparations are safe if standard precautions are followed (89H249; 90OS129; 93T2151). Elemental fluorine diluted with argon or nitrogen for safety is available commercially.

III General Properties and Spectra

The N-fluoropyridinium salts are crystalline species with melting points ranging from 90 °C for 1c to above 300 °C for 1e (86TL3271). With the notable exception of perchlorates, such as 1f, they are shock-resistant, thermally stable, and nonhygroscopic. Care must be taken in work with the perchlorates because in dry form they can undergo a violent explosion if touched, even with a soft Teflon spatula (94UP1).

The salts are stable indefinitely when stored under strictly anhydrous conditions. The solutions in dry degassed dichloromethane, tetrahydrofuran, or acetonitrile are also relatively stable. The salts undergo a slow decomposition when dissolved in dimethyl sulfoxide, N,N-dimethylformamide, alcohols, or water (94UP1). For example, a half-life of 13 days for the triflate 1b in D2O at room temperature has been reported (90OS129). Tertiary amine-mediated decomposition is rapid at room temperature.

In contrast to the cyclovoltammetric and polarographic reversible reduction of N-alkyl pyridinium salts to the corresponding radical (89JA5185), the electrochemical reduction of N-fluoropyridinium salts is irreversible (92T1595). Theoretical calculations strongly suggest the initial electron transfer to the π-system rather than to the nitrogen–fluorine bond (94UP2). Facile reduction is consistent with the high oxidation power of N-fluoro-pyridinium salts. Oxidation of colorless iodide ion to elemental iodine in the presence of starch to enhance the color of iodine is widely used as a convenient test for the presence of N-fluoropyridinium salts (90TL7379).

The stability of the nitrogen–fluorine bond (58MI1) and the nature of the N-fluoropyridinium cation have been discussed in terms of back-donation of p-electrons on the fluorine atom to the positive ring nitrogen (69MI1). The 1H and 19 F NMR spectra are fully consistent with the presence of a free cation. This conclusion comes primarily from the analysis of the spectra of 1b–g containing different counteranions. In particular, the fluorine chemical shift δ = 48.6 ± 0.2 in CD3CN with CFCl3 as internal standard has been noted for all derivatives (1b–g). The 19 F chemical shifts are sensitive to substituents at the pyridinium ring. Electron-donating groups cause upfield shifts, and the presence of electron-withdrawing groups results in deshielding. The only known exception is the cation of 4, in which the two methoxycarbonyl groups in the vicinity of the fluorine cause an upfield shift to δ = 25.5, apparently as a result of the anisotropic effect of the carbonyl groups (86TL3271; 89JOC1726). The mass spectra obtained by the SIMP method show a molecular ion peak corresponding to N-fluoropyridinium cation as the most intense peak (86TL3271; 94UP1).

IV Reactivity

A MECHANISTIC ASPECTS

The N-fluoropyridinium cation is a multicenter electrophile with several potential sites for reactions with nucleophiles or bases (Scheme 1). The X-philic attack at the fluorine atom is analogous to SN2 substitution at a carbon atom, and it has been suggested to be operative in fluorination of nucleophilic species by N-fluoropyridinium salts (82CRV615; 92T1595). However, evidence has been accumulating recently that the singleelectron transfer (SET) process may be the major reaction pathway in the fluorination of a vast majority of organic substrates (90JA8563; 92T1595). Single-electron transfer, nucleophile addition, and proton abstraction are all important processes in the syntheses of substituted pyridines. The charge concentration at the pyridinium nitrogen atom may be responsible for the preferential addition of nucleophile at the 2 position observed in a vast majority of known cases as well as the exclusive proton abstraction at this position of the N-fluoropyridinium cation. Synthetically useful transformations that have been suggested to involve these mechanistic pathways are discussed in the following sections.

B FLUORINATION REACTIONS

1 General Remarks

Recently, reagents and methods for selective introduction of fluorine into organic substrates have been of immense interest [81AG(E)647; 86CRV997; 87T3123; 88ACR307; 89MI1; 93T9385]. Substituted N-fluoropyridinium salts have become useful fluorination reagents which, regardless of the mechanism of fluorination, are often regarded as a formal source of electrophilic fluorine. Similar reagents that contain the electrophilic N–F function are N-fluoroquinuclidinium fluoride [88JCS(P1)2805], N-fluorosulfonamides (88TL6087), N-fluorosulfonimides (87JA7194), and N-fluoropyridin-2(1H)-one (83JOC761). This class of compounds is less expensive, more convenient, and/or safer in handling than the majority of other fluorinating agents—trifluoromethyl hypofluorite CF3OF (80-NJC239), phenyliodonium difluoride PhIF2 (82TL1165), trifluoroacetyl hypofluorite CF3COOF (80JOC672), acetyl hypofluorite CH3COOF (85-JOC4753), cesium fluorosulfate CsSO4F (88T6505), or xenon difluoride XeF2 (88JFC415), to name a few. The electrophilic fluorinating power (ease of fluorination) of N-fluoropyridinium salts increases with increasing positive charge at the ring nitrogen. Variation in the electronic effects of...