Neal O. Brace

Syntheses with perfluoroalkyl radicals from perfluoroalkyl iodides. A rapid survey of synthetic possibilities with emphasis on practical applications. Part one: alkenes, alkynes and allylic compounds

Abstract This review concerns the free radical chemistry of perfluoroalkyl iodides (R F I) in the synthesis of organic substances of a large variety of structures. Radical chain reactions of R F I are readily initiated by azonitrile initiators and this process generally gives pure products from unsaturated compounds of many types; the process is called iodoperfluoroalkylation. In the synthesis of fluorine containing organic compounds, few methods can compare with the efficiency, cost, selectivity and versatility of free radical addition of R F I. Part one reviews all aspects of the generation of R F radicals from R F I for synthetic purposes and reports the relative reactivity of R F I and of 20 typical alkenes or alkynes. Practical syntheses of 16 different classes of alkenes and alkynes are illustrated by examples and comprehensive tables of experimental data. Special emphasis is given to novel and important uses for many of these new perfluoroalkyl-substituted compounds. The aim of this review is to bring together in one place the results of research with R F I as an entry into the synthesis of fluorine containing organic compounds, over a fifty year time span. Additional classes of compounds are treated in subsequent parts of this review.

Some approaches to the synthesis of fluorinated alcohols and esters. II. Use of F-alkyl iodides for the synthesis of F-alkyl alkanols

Abstract Free radical addition of an F-alkyl iodide (RFI) to an alkenol or ester, followed by appropriate reduction is an efficient method for preparing the corresponding F-alkyl-alkanols of the homologous series, RF(CH2)n−OH. When n = 2,4 or higher, the two steps take place smoothly. The 1,2,3-substituted systems RFCH2CHYCH2Z, however, are susceptible to surprising difficulties. Reduction of RFCH2CHICH2ON to RF(CH2)3OH by hydrogen and catalyst (strong base acid acceptor), can be done either in one step or via RFCHCHCH2OH; however, dehydrohalogenation may also give the epoxide, and reduction in this case leads to the secondary alcohol, RFCH2CH(CH3)OH. By contrast, reduction of RFCH2CHICH2OAc by tributyltin hydride or with hydrogen over palladium (diethylamine acid acceptor) goes smoothly. Zinc and acid reduction of RFCH2CHICH2OAc gives elimination to RFCH2CHCH2; even RFCHCICH2OH gives RFCHCCH2 besides RFCHCHCH2OH. RFCHCICH2CH2OH, however, with zinc and acid is reduced cleanly to RFCHCHCH2CH2OH.

Syntheses with perfluoroalkyl iodides. Part II. Addition to non-conjugated alkadienes; cyclization of 1,6-heptadiene, and of 4-substituted 1,6-heptadienoic compounds: bis-allyl ether, ethyl diallylmalonate, N,N′-diallylamine and N-substituted diallylamines; and additions to homologous exo- and endocyclic alkenes, and to bicyclic alkenes

Abstract Non-conjugated dienes, with an azonitrile initiator, add one or two RFI to provide RFRH “diblock” and RFRHRF “triblock” compounds with one, or two perfluoroalkyl groups, respectively. Those diblock products with long fluorocarbon and hydrocarbon segments furnish novel surfactants for fluorocarbon liquid systems, and are cell structure modifiers for biochemical applications. In the case of 1,6-heptadiene, the perfluoroalkyl radical adds first to one end, and the adduct radical may transfer iodine from RFI to give RFCH2CHI(CH2)3CHCH2 (3). Or intervention of cyclization may intervene and the radical that is formed transfers with RFI to give cis- and trans-1-iodomethyl-2- (perfluoroalkyl)methylcyclopentanes (9a,b; Scheme. 2 ). AIBN initiates the free radical cyclization of 6-iodo-1-heptene, or of 3, to the cyclopentane derivatives; e.g., 9a,b from 3. Reductive cyclization of 3, and closely related iodoalkenes is induced by zinc and acid or by BuSnH4. From the ratio of linear to cyclic products in the two series ( Scheme. 3 ) some approximate rates of cyclization are deduced. N,N′-Diallylamine adds RFI with cyclization (azonitrile) to give an iodomethylpyrrolidine ( Scheme. 6 ) that oligomerizes by aminium salt formation. Other 1,6-heptadienoic compounds listed in the title give cyclization to five-membered ring products. exo-Cyclic and endo-cyclic alkenes elicit surprising responses to a range of reaction conditions and initiating systems. Of endo-cyclic alkenes, cyclooctene is the most, and cyclohexene is the least reactive towards addition of RFI. Cyclohexene adducts with RF groups from CF3 or (CF3)2CF to CF3(CF2)6 have structures and properties that differ significantly. The preferred conformation of the adducts varies with the RF group whether the configuration is cis- or trans. Of these adducts, only the trans-CF3I chair conformer undergoes normal equilibration. In the trans-adduct, the axial-CF3CF2 group cannot freely rotate over the ring because of axial hydrogen repulsions, and the 19 F NMR spectrum gives two sets of lines with relative intensities of 3:2. trans-A and cis-B cyclohexene adducts ( Scheme. 8 ) give 19 F NMR spectra with three resonance peaks from two non-equivalent CF3 groups of the iso-perfluoropropyl group coupled to each other and to the CF group. Non-equivalence of the two CF3 groups is attributed to proximity of the CF3CFCF3 group and the large, adjacent iodine atom. Removal of iodine removes non-equivalency of the CF3 groups. Thermolysis of adducts A–D gives an equilibrium mixture of the cis/trans-isomers from which entropy and the energy content are determined. Addition of RFI to cyclohexene by SET initiation with copper gives adducts in good yield. Norbornene, or substituted norbornenes, and norbornadiene add RFI in a facile reaction initiated by azonitrile, peroxide or the SET method ( Scheme. 14 ).

Some approaches to the synthesis of fluorinated alcohols and esters. III. Synthesis of 2-(F-alkyl)ethanols from 2-(F-alkyl)-1-iodoethanes and amides.

Abstract 1-Iodo-2-(F-alkyl)ethanes, R F CH 2 CH 2 I, when heated with a large excess of N-methylformamide (NMF) give in high yield, mixtures of predominately R F CH 2 CH 2 OH, some formate ester and a little R F CHCH 2 . In a study of this process, significant variables were examined, including solvent, reactant ratio, effect of water, and alternative amide reactants. The coproduct from NMF is the amidine salt, [MeNHCH(NHMe)] + I − . By contrast, R F CH 2 CH 2 I with N,N-dimethylformamide (DMF) and water (one or two mols) gives chiefly the formate ester; the coproduct is Me 2 NH 2 + I − . A mechanistic scheme is proposed: in the first step, an alkyl imidate salt, e.g., [HC(NH Me)OCH 2 CH 2 R F ] + I − is formed by O-alkylation of NMF; reaction of the imidate with more NMF gives a tetrahedral intermediate that breaks down rapidly to R F CH 2 CH 2 OH, and HC(NHMe)NMeCHO + I − . The formate ester is derived from the alcohol and this N-formyl acylating agent, in a subsequent step. Analogously, the alkyl imidate salt from DMF and R F CH 2 CH 2 I reacts with water as nucleophile (but not with DMF) to give a tetrahedral intermediate that cleaves under stereoelectronic control to formate ester and amine salt, but not to alcohol. Quantitative isolation of amine salt and amidine salt, and observed rates of reaction give solid support to this proposed mechanism.

Oxidation chemistry of perfluoroalkyl-segmented thiols, disulfides, thiosulfinates and thiosulfonates: The role of the perfluoroalkyl group in searching out new chemistry

Abstract The oxidation chemistry of perfluoroalkyl-segmented thiols, R F –R–SH ( 1 ), thiosulfinates, R F –R–S(O)S–R–R F ( 3 ), thiosulfonates, R F –R–S(O 2 )S–R–R F ( 4 ) and disulfides, R F –R–SS–R–R F ( 5 ) (in which R F = n -C 6 F 13 or n -C 8 F 17 and R=CH 2 CH 2 ) is studied herein. Base catalyzed reaction of C6 thiol 1 with hydrogen peroxide gives pure disulfide 5 , quantitatively. Other, less suitable methods for the oxidation of thiol 1 are also examined and compared. Selective oxidation of disulfide 5 by peroxy acids in chlorinated solvents gives excellent yields of thiosulfinate 3 . Unlike their hydrocarbon analogues, which are unstable to heating or storage, the R F -segmented thiosulfinates 3 are relatively stable, crystalline compounds. Selective oxidation of 3 by sodium metaperiodate gives thiosulfonate 4 in high yield. Side reactions intervene with unfavorable conditions, or when peroxy acetic acid in acetic acid is used as oxidant,. Oxidation of 5 by hydrogen peroxide in low conversion gives 4 and two new compounds, 8 and 9 . Compound 8 is n -C 6 F 13 S(O) 2 CH 2 CH 2 C 6 F 13 (probably the sulfinate ester and not the sulfone), and 9 is most likely the O , S -sulfenyl sulfinate or, possibly an isomer, the vic-disulfoxide. A free radical chain mechanism is proposed for conversion of 4 (or 9 ) to 8 . Compounds 8 and 9 are stable in solution and are identified by MS/GC. In 3 , 4 and 5 , the ν CH bands correlate with NMR of CH 2 at C(1) and C(2) positions, both 1 H and 13 C NMR. The R F -segment in these unique sulfur compounds enhances their utility and modifies their chemical and physical properties in important and interesting ways.

Some approaches to the synthesis of fluorinated alcohols and esters. I. Completely fluorinated esters from the hunsdiecker reaction of silver F-alkanoates with iodine

Abstract A completely fluorinated ester of the type RFCO2CF2RF′ was obtained from reaction of silver 3,6,9-trioxa-F-undecanoate and iodine with a diluent at 130°. This new substance resembled closely the previously prepared 1,1-dichloro-F-alkyl esters and was hydrolytically and thermally labile. Substitution products, RFCOY (Y = nucleophile) and pyrolysis products, RFCOF and RF′COF were isolated and characterized. It appears probable that the acyl hypoiodite and the iodo-F-alkane reacted by an SEi-type process to give the completely fluorinated ester.

Reaction of 1-(F-alkyl)-2-iodoethanes with amides for the synthesis of RFCH2CH2OH: A mechanistic study

Abstract Alkylation of formamide or N-methylformamide (NMF) by alkyl halides (RCH 2 X) was studied as a mild, non-hydrolytic method for the synthesis of alcohols. Thus, 2-(F-hexyl)-1-iodoethane (R F CH 2 CH 2 I, 1 , RFC 6 F 13 ) with NMF gave 2-(F-hexyl)-1-ethanol ( 2 ) and formate ester ( 3 ) in a combined yield of 93–99.5 %, which is much higher than in most hydrolytic or substitutive processes with 1 . None of the dialkyl ether was formed. Mechanism of reaction involved the rate-determining formation of HCNH(Me)OCH 2 R + I − ( 4 ,HI). This imidate salt reacted with nucleophiles, including NMF, to give 2 , 3 and MeNHCHNHMe + I − . Similar reaction of 1 with N,N′-dimethylformamide (DMF) and water gave 2 (33 %) and 3 (66 %), and coproduct Me 2 NH 2 + I − . No reaction occurred without water. Accordingly, the imidate salt from 1 and DMF is susceptible to attack by a small nucleophile such as water, but not by DMF. These conclusions were confirmed by a study of 1-bromooctane and 1-iodooctane with formamide and with NMF. Rates of formation of products (1-octanol, 1-octene and di-n- octyl ether) and of imidate salt were obtained under several reaction conditions. The coproduct amine salt was not RNH 3 + X − (R = Me or H) as previously thought, but a methanimidamide salt HCNR(NH 2 R) + X − .

Synthesis of 2-(F-alkyl)ethanols and esters by phase transfer catalyzed SN2 reactions of 2-(F-alkyl)-1-iodoethanes

Abstract R F CH 2 CH 2 I (1) reacted well with carboxylate ions in liquid/liquid two phase systems. The S N 2 product, an ester (5) and the E-2 product, an alkene (4) were determined quantitatively in a careful study of several reaction parameters. Conversion of 1 reached 99% in 24 h at 90° and selectivity to ester (5/4) varied with nucleophilicity (basicity) of RCOO − . The weaker the base the slower the reaction, and the higher the selectivity. Values of 5/4 were: R  CF 3 , 12; NCCH 2 , 10; H, 2.3; CH 2 CH, 1.7. In a series of comparable basicity (K a of RCOOH = 1.5 to 2.2 x 10 −5 ), the branched ions were superior to short and straight chaine substances. 5/4 were: R  CH 3 , 0.6; CH 3 CHCH, 2.0; n-Bu, 1.3; and i-Bu, 2.76. KOAc vs. KO 2 CHMe 2 and 1 gave isobutyrate/acetate ester of 8.9. In these reactions toluene was better than octane as solvent. Several phase transfer catalysts (PTC) were evaluated. Reactions run in a dipolar, aprotic solvent gave highly inferior results. 1 with KOAc or with KO 2 CHMe 2 gave varying amounts of reaction, but mostly E-2 product. For KOAc 5/4 was 0.28 to 0.19. Catalysts such as ‘18-Crown-6’ decreased further the selectivity. However, it is believed that phase transfer processes can be improved further.

Some approaches to the synthesis of fluorine-containing alcohols and esters

Abstract Among F-containing alcohols only trifluoroethanol, the so-called ‘telomer alcohols’ [H(CF2CF2)nCH2OH], and certain esters of 2-(F-alkyl)ethanols and 3-(F-alkyl)propanols, have achieved commercial importance. Their utilization has been limited by lack of suitable methods of synthesis and by their high cost. Yet F-containing alcohols and their esters have unique properties, and comprise a versatile class of compounds. It is to be noted that completely fluorinated esters have recently become available. F-substituted alcohols must be made by special, less well-known methods. Routes based on tetrafluoroethylene (TFE) as starting material are of current interest. F-alkyl iodides (RFI) are made in two steps from TFE. Reaction of RFI with ethylene gives 2-(F-alkyl)-1-ethanes, and under suitable conditions, higher telomers in high yield. Displacement of iodine of RFCH2CH2I by an acyloxy group gives an ester, such as acrylate or fumarate of the F-substituted alcohol. Several methods have been discovered for this process, most recently by reaction with N-methylformamide or N,N-dimethylformamide and water. Free radical addition of RFI to vinyl acetate and subsequent reduction provided 2-(F-alkyl)ethanols in excellent yield. Similar steps using allyl acetate gave both 3-(F-alkyl)-1-propanols and 3-(F-alkyl)-2-propanols; the latter compound also was formed by hydrolysis of the initial adduct. These various methods will be outlined and some recent results in a study of O-alkylation will be presented. Support by the Central Research Group, Ciba-Geigy Corp., Ardsley, N.Y. is gratefully acknowledged.

Free radical addition of F-alkyl compounds to unsaturated carboxylic anhydrides and their derivatives

Abstract Many perfluoroalkyl-substituted organic compounds have been obtained through free radical addition of F-alkyl iodides to a center of unsaturation: X, Y, and Z may include carbon chains, rings and various substituents. During the course of these synthetic studies—done over a span of several years—significant discoveries in mechanism and structure have been made. Today I wish to report some free radical additions of F-alkyl iodides to unsaturated anhydrides and their derivatives. Among the compounds recently discovered are the norbornene products 5 to 10. Spectroscopic properties of the adducts varied with position and nature of the substituents. Somewhat surprisingly, the chemical shift of protons on the R F side of the molecule was affected by changes in substituents on the other side of the molecule. Various reactions of the adducts were studied. Unusual stereospecificity in lactone formation and in base- induced cyclization to nortricyclene derivatives was observed. Only when the iodo group was in an endo position did these reactions occur. Analogous free radical addition of fluorinated thiols (R F CH 2 CH 2 SH) to norbornene anhydrides produced a series of 5-polyfluoroalkylthionorbornane-2,3-dicarboxylic acid anhydrides(11, 12; U S Patent 3,989,725 (1976). As in previous studies the entering group took up the exo position exclusively. Reaction with acids, esters or norbornene carboxylic imides of the fluorinated thiol also gave analogous products. Because of the hydrophobic nature of the F-alkyl groups the entire range of compounds displayed pronounced surface-activity and would appear to have utility in a wide range of applications.