Chemistry of fluoroalkyl cyanides

This review is devoted to the chemistry of fluoroalkyl cyanides (RF-nitriles): their synthesis and chemical properties. Syntheses of non-functionalized RF-nitriles (FCH2CN, F2CHCN, CF3CN, C2F5CN, FCH2CH2CN, etc.) and dinitriles (NCCHFCN, NCCF2CN, NCCF2CF2CN, etc.) are considered. The synthesis of functionalized RF-nitriles such as F2NCF2CN, F2NCClFCN, Cl2CFCN, Br2CFCN, (O2N)2CFCN, O2NCF2CH2CH2CN, and dinitriles, such as O(CF2CN)2, NCCF2N=NCF2CN, is also considered. RF-Nitriles are attractive electrophilic, enophilic, and dienophilic building-blocks: they were used in the synthesis of various fluorine-containing heterocyclic compounds, such as RF-bearing pyridines, 1,3,5-triazines, tetrazoles, and others. RF-nitriles were also used in the synthesis of unusual acyclic compounds, such as fluoroalkylated N,N-difluoroamines, F2NCF2CF2N=SF2, RFimino esters, and others.


Introduction
Fluorinated organic compounds attract much interest due to their unique physicochemical properties, biological activities, and because they are of great importance in medicine. [1][2][3][4] An electron-withdrawing R F group bonded to a carbon atom that belongs to a double or triple bond, or a conjugated system, significantly increases the electrophilic, dienophilic and dienic (in the case of a conjugated system) properties of the molecule. 5,6 Fluoroalkyl cyanides (R F -cyanides, R F -nitriles) are a group of unique compounds, where a fluoroalkyl group is bonded to the highly polarized C≡N group. This fact dramatically increases the electrophilic as well as dienophilic properties of the C≡N group.
R F -cyanides (R F CN) can be divided into two groups: non-functionalized R F -cyanides and functionalized R Fcyanides. In non-functionalized R F -cyanides, the R F group contains only atoms of sp 3 hybridized carbon, as well as atoms of fluorine and, optionally, hydrogen. In functionalized R F -cyanides, the R F group besides sp 3 -C, F, and, optionally, H, contains at least one non-fluorine heteroatom or an sp 2 (sp)-C (a double/triple bond). Those non-functionalized R F -cyanides, which don't have a hydrogen atom in their R F groups, are perfluoroalkyl cyanides.
Trifluoroacetonitrile, CF3CN, the parent perfluoroalkyl cyanide, is a symmetric top molecule. The measured dipole moment μ = 1.262 ± 0.010 D (measurements were made in a Stark-modulated microwave spectrometer). 7 The enthalpy of formation of CF3CN is ˗118.9 kcal/mol. 8 The vibrational spectrum of this compound was originally assigned by Edgell and Potter. 9 The lowest frequency vibrational mode of this molecule was measured at 192 cmˉ1 and is assumed to be the -C-C≡N bond. Owing to the large dipole moment and the large thermal population, the spectra are intense and it is relatively easy to observe spectra in the excited vibrational state v8 = 2. Physical properties of trifluoroacetonitrile such as critical temperature (311.11 K), critical pressure (524.75 lbf -2 ), and critical density (0.470 g cm -3 ) were measured. 10 Thermodynamic properties of trifluoroacetonitrile from 12 K to its boiling point (˗67.68 °C) were explored. 11 High resolution IR spectra over a range of temperatures from ˗80 to 250 °C of gaseous CF3CN were published in 1970. 12 The rotational spectra of the ground state and some excited states of CF3CN have been studied by several authors. [13][14][15][16][17][18] The nuclear quadrupole hyperfine structure observed in the ground vibrational state has been the subject of Fourier transform work by Cox et al. 19 The rotational spectra of CF3CN for transitions at Jʹʹ = 16, 18˗21, and 32  were recorded at ˗78 o C (P ~0.01 torr). 20 These spectra are complex, similar to the spectra of CF3C≡CH in the v10 = 2 state, 21 having a superposition of three series for each Jʹʹ corresponding to l = 0 and l = ± 2 (kl > 0 or k < 0). 20 The effect of electrode surface roughness on the breakdown characteristics of C3F7CN/CO2 gas mixtures was explored: these mixtures are considered as a potential alternative for replacing SF6 in high voltage power equipment. 22 The proton affinities of R F -nitriles such as CF3CN (695 kJ/mol), CF3CF2CN (699 kJ/mol) and CF3(CF2)2CN (700 kJ/mol) were estimated. 23 R F -nitriles are able to form complexes with atoms and molecules, and adducts with anions. Thus, the rotational spectrum of the weakly bound (van der Waals) complex CF3CN-argon has been observed and assigned. 24 The structure of this complex is T-shaped with a center of mass separation of 3.73 Å. 24 Centrifugal distortion analysis yields a weak bond stretching force constant of 1.92 Nmˉ1. 24 The CF3CN-H2O complex has been studied by pulsed-nozzle Fourier transform microwave spectroscopy. 25 The rotational constants, centrifugal distortion constants, and the 14 N nuclear quadrupole coupling constants have been determined. The complex is T-shaped, with the oxygen atom of the water located 3.135 Å from the carbon atom of CF3 of

Dehydration of R F -amides
In 1922, Swarts described the preparation of trifluoroacetonitrile (N1) by dehydration of trifluoroacetamide (1) with phosphorus anhydride at 145-150 o C. 28 In 1943, Gilman and Jones used essentially the same method for the preparation of trifluoroacetonitrile (74%), collected the product as a colorless liquid in a dry-iceacetone trap (Scheme 1). The compound boiled at ˗63.9 o C (743 mm Hg). 29 Similarly, difluoroacetonitrile, F2CHCN, was prepared from difluoroacetamide and P4O10. This nitrile was isolated as a liquid that boils at 22 o C. 30 Scheme 1. Preparation of trifluoroacetonitrile (N1) from trifluoroacetamide (1) and P4O10.
The first synthesis of fluoroacetonitrile (N2) was published by Swarts in 1922 who claimed that it was necessary to distil the amide with phosphoric anhydride under reduced pressure and to collect the distillate at ˗50 o C. 31 In 1949, Buckle et al. used a similar approach to the synthesis of fluoroacetonitrile (65.2%) from fluoroacetamide (2) (Scheme 2), for its toxicity testing. 32 The toxicity of fluoroacetonitrile on inhalation proved to be lower than that of methyl fluoroacetate because the nitrile is not hydrolyzed in vivo to the toxic fluoroacetic acid. [32][33][34] Scheme 2. Preparation of fluoroacetonitrile (N2) from fluoroacetamide (2) and P4O10.

Trimerization
Heating trifluoroacetonitrile (N1) in the presence of other compounds often leads to trimerization and the formation of 2,4,6-tris(trifluoromethyl)-1,3,5-triazine (88). 78,79 Therefore, heating CF3CN in the presence of reagents less reactive towards CF3CN can cause the formation of some amounts of 88. Thus, CF3CN doesn't react with tetrafluorohydrazine, N2F4, at 100˗220 o C, but in the presence of this reagent converts at these temperatures to triazine 88 in 100% yield (Scheme 58). 78 Similarly, in the presence on an imine, nitrile H(CF2)2CN gives some amounts of the corresponding HCF2CF2-triazine as a by-product (see paragraph 3.3.3, Scheme 102). 79 Scheme 58. Trimerization of trifluoroacetonitrile (N1). It was also reported that fluoroacetonitrile (N2) 81    The suggested plausible mechanism of the formation of the above mixture of products involves the dissociation of the starting compounds at 515 o C to free radicals F3C·, NC·, F·, F2N·, and the recombinations of the latter. 78 Trifluoroacetonitrile (N1) doesn't undergo the trimerization at room temperature and can react with various reagents. Thus, the reaction of CF3CN with N2F4 at room temperature under UV light produces for 48 hours C2F5NF2 22 in 85% yield (Scheme 63). 78 Scheme 63. Synthesis of N,N-difluoro(perfluoroethyl)amine 22 from CF3CN N1 and N2F4.

Reactions with halogens.
The first direct fluorination of R F -nitriles was published in 1959. 84 84 Direct fluorination of trifluoroacetonitrile with F2/N2 at 140 o C gave a mixture of CF4, C2F6, C2F5NF2, CF3CF=NF, CF3N=NC2F5, and C2F5N=NC2F5. The CF3CF=NF was obtained pure by analytical chromatography. 85 Direct fluorination of CClF2CN with F2/N2 at 140 o C yielded a crude product, which was rectified, and thus pure samples of CCIF2CF2NF2, CClF2CF2N=NCF3, and CClF2CF=NF were obtained. 85 The fluorination of CClF2CN at 175 o C yielded a product, which contained CF4, NF3, CClF3, C2F5Cl, and trace amounts of CF3N=NCF3, and CClF2CF2NF2. 85 Trifluoroacetimidates 140-143 were prepared from the corresponding alcohols 136-139 by treatment with n-butyllithium followed by addition of an excess of trifluoroacetonitrile (N1) at ˗78 o C in THF. 104 Best yields were obtained using less than one mole equivalent of n-BuLi. The Various R F -imidates 148-162 were synthesized through the reaction of in situ formed R F -nitriles with benzyl alcohols in the presence of DBU. The obtained R F -imidates were purified by silica gel column chromatography and were stable for a month at room temperature (Table 10). 105 Similarly, treatment of R F -nitriles with (COCl)2/DMSO in the presence of Et3N at ˗78 o C, and the subsequent treatment of the reaction mixtures with an alcohol in the presence of DBU resulted in the formation of various perfluoroimidates 163 in 27-92% yield (Scheme 86). 106

Scheme 86. Synthesis of various perfluoroimidates 163.
Reaction of R F -nitriles with 1,2-epoxy-3-hydroxypropane (164) gave 2-R F -4-(hydroxymethyl)oxazolines 166-168 (via intermediate R F -imidates 165) in 46-93% yield (Table 11). BF3·Et2O can also be used as a catalyst to synthesize R F -isoxazolines. 107 The above R F -isoxazolines 166-168 can be used in the synthesis of fluorine-containing analogues of 2methyl-5-dimethylaminomethyl-2-oxazoline methiodide, which is the 2-oxazoline analogue of Fourbeau's dioxolane that equals acetylcholine in potency and belongs to the highly active cholinomimetics. 108 Heating 1-chloro-2,3-epoxypropane (169) with R F -nitriles at 150 o C in a glass-pressure tube in the presence of tetraethylammonium bromide as the catalyst led to the formation of the corresponding R F -oxazolines 172-174 in moderate yields. 109 The suggested plausible mechanism involves the nucleophilic addition of The reaction of trifluoroacetonitrile (N1) with carboxylic acids was reported in 1963. 110 Analytically pure imides: trifluoroacetyltrifluoroacetimide, (CF3CO)2NH (176) and acetyltrifluoroacetimide, CH3CONHCOCF3 (177), were synthesized from trifluoroacetonitrile (N1) and the corresponding carboxylic acids. The authors believe that the reaction of CF3CO2H with CF3CN proceeds through four-membered cyclic intermediate 175 (Scheme 88). 110 Imide 177 is a relatively unstable compound: it slowly decomposes to a mixture containing CF3CO2H and MeCN (Scheme 88). 111 Dialkyl phosphites 276 and 277 reacted with difluoroacetonitrile and trifluoroacetonitrile in the presence of catalytic amounts of a nitrogen base at room temperature to form iminophosphonates 278-280 in high yields. 133 In solution, imidoyl phosphonates 278-280 exist as equilibrium mixtures of the Z/E-isomers, the more sterically hindered Z-configuration being thermodynamically preferable. The Z/E ratio essentially depends on the R F substituent at the C=N bond, but it is practically independent of the nature of the phosphonyl group (Scheme 116). 133

Scheme 116. Synthesis of imidoyl phosphonates 278-280.
Less nucleophilic diphenyl phosphite (281) reacts with fluorinated nitriles in the same manner to afford imidoyl phosphonates 282 and 283, as a dynamic mixture of Z/E-isomers. 133 Iminophosphonates 282 and 283 undergo partial dissociation to the initial compounds on storage at room temperature. 133 Diphenyl phosphite, formed upon dissociation, quickly adds to the activated C=N bond of the starting iminophosphonates to form stable geminal bisphosphonates 284 and 285, which are the desired products of this reaction (Scheme 117). 133 A series of trihaloacetonitriles, bearing a different number of fluorine and chlorine atoms in the molecule, were also investigated in the above reaction.  The Diels-Alder cycloaddition of R F -nitriles and 1,2-butadiene proceeds at 400 o C to give R F -pyridines 309 in 97-99% yield (R F = CF3, C2F5, CF3CF2CF2) and 12% yield (R F = CClF2) (Scheme 123). 138 Scheme 123. Diels-Alder cycloaddition of R F -nitriles and 1,2-butadiene.
The low yield in the case of ClCF2CN N141 might be explained by the fact that this nitrile decomposes at high temperatures into difluorocarbene and ClCN, that has been proven through the formation of tetrafluoroethylene and isolation of the CF2 addition product 310 (Scheme 124). 139

R F -nitriles as active methylene compounds
Fluoroacetonitrile and its α-monosubstituted derivatives are active methylene compounds, which can be used in various synthetic strategies for the preparation of fluorine-containing substances. Thus, the reaction of fluoroacetonitrile with ethyl formate in the presence of KOBu t gave potassium (Z)-2-cyano-2-fluoroethenolate (360) (77%) (Scheme 141), 35 an attractive and readily available building-block for the synthesis of fluorinated heterocycles such as fluorinated pyrimidines and pyrazoles. 151 The approach was expanded by using of various bases such as KOBu t , NaOBu t , NaOAmyl t , NaHMDS, and methyl/ethyl formates, that allowed preparation of sodium and potassium (Z)-2cyano-2-fluoroethenolates in 35-79% yield. No target product was isolated when such bases as NaOMe, NaH, KOEt were used. 35  152 Aliphatic aldehydes don't allow preparation of 1-cyano-1fluoroalkenes, producing complex mixtures (Table 13). 152  The use of fluoroacetonitrile in the Horner-Wittig reaction allows preparation of α-fluoro acrylonitriles. The reaction of FCH2CN with Ph2P(O)Cl leads to the formation of nucleophilic anions 369, which then react with aldehydes and ketones to give α-fluoro-α,β-unsaturated nitriles 370, which were isolated in 31-73% yield (Scheme 142). 153 Scheme 142. Synthesis of α-fluoro-α,β-unsaturated nitriles 370.

Conclusions
Thus, fluoroalkyl cyanides, attractive electrophilic, enophilic, and dienophilic building-blocks, can be synthesized via a large variety of synthetic methods, that makes them both synthetically valuable and readily available reagents. R F -Nitriles are versatile reagents: They can react with electrophiles at the C≡N group to produce various unusual reactive structures, they can play role of active methylene compounds, and they can be used as highly reactive building-blocks in cyclizations for the syntheses of fluorine-containing heterocyclic compounds. Fluoroalkyl cyanides are important reactants in medicinal chemistry for the design, development, and synthesis of pharmaceutical drugs.