# Patent

## Title
Synthesis of carbon-labeled perfluoroalkyl compounds

## Abstract

Various 13C and 14C carbon labeled compounds

Rf—bCF(U)y(T)zFormula 1A or

Rf—bCF2bCF(U)y(T)zFormula 1B

wherein

    
    
        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        m is 1, 3 to 20, or a mixture thereof;
        Z is F when m is 1, and Z is F, Cl, or H when m is 3 to 20 or a mixture thereof;
        b is 13 or 14;
        y is 1, and z is 0 or 1; and
        
            when y and z are each 1, U is F, and T is selected from the group consisting of monovalent radicals —X wherein X is I or Br, —CH2—CH2—X, —CH═CH2, —CH2—CH2—OH, —CH2—COOH, —CH2OH, —bCH2OH, —COOH, —bCOOH, —O—CF(CF3)—C(O)F, —O—CF(CF3)—X, —SO2Y wherein Y is H, F or Cl, and —SO3H; and
            when y is 1, and z is 0, U is selected from the group
        
        
        consisting of divalent radicals ═CH—COOH, ═CH—CH2—OH, and ═O, are disclosed, and a process for their preparation which selectively introduces 13C and 14C carbon labels into a fluoroalkyl chain.

## Background
BACKGROUND OF THE INVENTION
There is an interest in determining the environmental and biological fate of various perfluoroalkyl compounds, including their partial decomposition products. There is as well a need for carbon labeling, which enables distinctive analytical monitoring for studying reaction kinetics and mechanisms. Perfluoroalkyl iodides (CnF(2n+1)—I) are important reactive intermediates in the chemistry of perfluoroalkyl compounds. The most widely used commercial route to prepare them consists of the telomerization of tetrafluoroethylene. This reaction generates the family of perfluoroalkyl iodides C2nF(4n+1)-I having an even number of carbon atoms, thus making them easily available for general synthetic use and further functionalization. For the studies described, 13C- and 14C-carbon labeled (or enriched)perfluoroalkyl or partially fluorinated alkyl derivatives are needed, wherein the labeled carbon atom is in the perfluoroalkyl group instead of within the hydrocarbon portion of the molecule. Having the labeled carbon in the perfluoroalkyl group would be advantageous because a perfluoroalkyl chain is chemically inert, and thus the carbon label would still remain a part of the partially fluorinated molecule even with the molecule's partial decomposition or conversion to other intermediates. Additionally, this stability would allow easy molecular recognition and detection in complex reaction mixtures or biological media.
Hereinafter the term “labeled” as applied to a carbon atom means that the concentration of 13C or 14C isotopic content has been significantly enriched. Commercial sources of labeled materials, such as barium carbonate-13C, are available with a 98 percent 13C atom enrichment. Among the 14C sources, barium carbonate-14C with higher than 50% (31.3mCi/mmol) enrichment for 14C atom is used. The 14C isotope is radioactive, undergoing beta-decay with half-life of about 5700 years. Carbon-labeled compounds can be blended into the corresponding unlabelled (12C) compound for studies or analytical detection, a procedure known as “spiking”. Thus, the compounds with high (50-99%) isotope concentrations are preferred.
However, the synthesis of specifically labeled 13C— and 14C-carbon perfluoroalkyl compounds presents many challenges. Common fluorinated building blocks such as tetrafluoroethylene are not available in carbon-labeled form. Carbon-labeled tetrafluoroethylene is also not viewed as practical for the synthesis of individual n-perfluoroalkyl labeled materials, since it requires special safety handling measures not easily attainable in the laboratory. It is prone to polymerization, and its telomerization would lead to the mixture of homologs X(CF2CF2)nY rather than a single molecule. There are also considerable laboratory limitations to achieve perfluorination with powerful fluorination agents, such as elemental fluorine F2, and electrochemical fluorination in liquid HF. These procedures are typically used on the industrial scale to make various perfluoroalkyl building blocks and their derivatives. It is desirable to perform such labeled syntheses primarily on the laboratory scale using ordinary laboratory equipment. The synthesis of such carbon-labeled target organic molecules primarily employs labeled carbon sources (such as 13 or 14CO2, and Na13 or 14CN) that are widely commercially available, or labeled hydrocarbon intermediates (ethylene, acetic acid, etc.) that are more expensive and limited in availability.
A possible synthetic route for the preparation of 13C- and 14C-labeled perfluoroalkyl iodides is the Hunsdieker reaction of CnF(2n+1)—COOAg salts with iodine. An example of such methodology is the preparation of 1-14C-1-iodoperfluoropropane [Seleznev, V. G.; Skorobogatov, G. A., Slezar, O. N. “Photolysis of 1-14C-perfluoropropyl iodide with powerful light pulses” J. Org. Chem. USSR (Eng. Transl.), 12, 1976, 259]. However, such an approach requires the multi-stage synthesis of the labeled hydrocarbon acid precursors, which are further perfluorinated. It requires electrochemical fluorination expertise, special equipment, and handling of liquid hydrogen fluoride, all of which present safety issues. Additionally, perfluorination of relatively long n-alkyl chain hydrocarbon derivatives, using electrochemical fluorination or other means, can be incomplete or be accompanied by isomerization of the labeled alkyl chain. Such mixtures would not be acceptable for the end use, and pure compounds and their isomers would be very difficult to separate.
For the environmental, biological, analytical and other programs described above, it is desirable to have an easy and safe method to selectively prepare 13C- and 14C-labeled perfluoroalkyl iodides and their derivatives wherein the labeled carbon is within the perfluoroalkyl chain.
The present invention provides a selective process for the preparation of such perfluoroalkyl iodides and derivatives having a labeled carbon atom in a specific and terminal location of the perfluoroalkyl group. The process provides access to defined labeled compounds instead of a mixture of isomers.
SUMMARY OF THE INVENTION
The present invention comprises a compound of

Rf—bCF(U)y(T)z  Formula 1A or

Rf—bCF2bCF(U)y(T)z  Formula 1B

wherein

    
    
        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        m is 1, 3 to 20, or a mixture thereof;
        Z is F when m is 1, and Z is F, Cl, or H when m is 3 to 20 or a mixture thereof;
        b is 13 or 14;
        y is 1, and z is 0 or 1; and
        
            when y and z are each 1, U is F, and T is selected from the group consisting of monovalent radicals —X wherein X is I or Br, —CH2—CH2—X, —CH═CH2, —CH2—CH2—OH, —CH2—COOH, —CH2OH, —bCH2OH, —COOH, —bCOOH, —O—CF(CF3)—C(O)F, —O—CF(CF3)—X, —SO2Y wherein Y is H, F or Cl, and —SO3H; and
            when y is 1, and z is 0, U is selected from the group consisting of divalent radicals ═CH—COOH, ═CH—CH2—OH, and ═O.
        
        
    
    


The present invention further comprises a process for the preparation of a compound of

Rf—aCF(U)y(T)z  Formula 1C

wherein

    
    
        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        m is 1, 3 to 20, or a mixture thereof;
        Z is F when m is 1 and Z is selected from F, Cl, or H when m is 3 to 20 or a mixture thereof;
        a is 12, 13 or 14;
        y and z are each 1;
        U is F; and
    
    


T is —X wherein X is I or Br,
comprising


    
    
        a) contacting a perfluoroalkyl metallic compound with aCO2 to generate the corresponding acid;
        b) contacting the acid from step a) with a fluorinating agent to yield Rf—aC(O)F;
        c) contacting the Rf—aC(O)F with a substituted trifluorooxirane in the presence of a fluoride ion source to yield Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F wherein R′′ is H or F and p is 1 to 8; and
        d) contacting Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F with a metal iodide or metal bromide and heating to yield Rf—aCF(U)y(T)z.
    
    


The present invention further comprises a process for the preparation of a compound of

Rf—bCF2bCF(U)y(T)z  Formula 1B

wherein

    
    
        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        m is 1, 3 to 20, or a mixture thereof;
        Z is F when m is 1 and Z is selected from F, Cl, or H when m is 3 to 20 or a mixture thereof;
        b is 13 or 14;
        y and z are each 1;
        U is F; and
        T is —X wherein X is I or Br,

comprising

        a) contacting a perfluoroalkyl metallic compound of formula

(Rf)(v-w)bCF2MXw 

wherein

        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        M is selected from the group consisting of Zn, Li, Cd, Mg, Ca, and amalgams thereof with Hg,
        X is I or Br,
        v is the valence of M,
        w is 0 or 1, and
        b is 13 or 14,
        with bCO2 to generate the corresponding acid;
        b) contacting the acid from step a) with a fluorinating agent to yield Rf—bCF2bC(O)F;
        c) contacting the Rf—bCF2bC(O)F with a substituted trifluorooxirane in the presence of a fluoride ion source to yield Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F wherein R′′ is H or F and p is 1 to 8; and
        d) contacting Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F with a metal iodide or metal bromide and heating to yield Rf—bCF2bCF(U)y(T)z.
    
    


The present invention further comprises a process for the preparation of a compound of formula

Rf—bCF2—bCOOH

wherein Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—, Z is F, and m is 3 to 20 or a mixture thereof, comprising contacting Rf—bCF2X wherein Rf is as defined above and X is Br or I with an organometallic compound R—Mg—X or R—Li wherein R is a C1-C4 alkyl and X is Br or I, and bCO2 to generate Rf—bCH2—bCOOH.



DETAILED DESCRIPTION
Trademarks are shown in upper case.
The term “labeled” as used herein is applied to a carbon atom where the concentration or isotopic content of 13C or 14C has been significantly enriched. The range of necessary enrichment differs for 13C and 14C enrichment since 13C, in contrast to 14C, occurs significantly in the natural environment, to the extent of about 1.1%. Thus for 13C labeling, the proportion of 13C at a specific atom location is at least about 50%, preferably at least about 90%, and most preferably at least 98%. For 14C labeling, the proportion of 14C at a specific atom location is at least about 10%, preferably at least about 25%, and most preferably at least 50%, with high radiochemical purity. The present invention provides isotopically labeled 13C- or 14C-labeled fluorinated compounds wherein a labeled carbon is within the perfluoroalkyl chain, and compounds having two or more labeled carbons present. The present invention further provides synthetic routes to make the desired labeled compounds maintaining the 14C/12C or 13C/12C isotope ratio equal or similar to the starting carbon-labeled material. The synthetic routes of the present invention also provide a process for extending the perfluoroalkyl chain of perfluoroalkyl halides CnF(2n+1)X wherein X is Br or I using stepwise fluorination of a terminal carboxy group of perfluoroalkyl carboxylic acids CnF(2n+1)—COOH, yielding the useful CnF(2n+1)CF2X halides. This extension of the perfluoroalkyl chain is useful with both labeled and unlabeled compounds.
This invention comprises isotopically 13C- or 14C-labeled fluorinated compounds with linear and branched perfluoroalkyl chains of the structure of Formula 1A or Formula 1B, and derivatives thereof;

Rf—bCF(U)y(T)z  Formula 1A

Rf—bCF2bCF(U)y(T)2  Formula 1B

wherein Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—, wherein m is 1, 3 to 20, or a mixture thereof; Z is F when m is 1 and Z is selected from F, Cl, or H when m is 3 to 20 or a mixture thereof; b is 13 or 14; y is 1, and z is 0 or 1; and

    
    
        when y and z are each 1, U is F, and T is selected from the group consisting of monovalent radicals —X, wherein X is I or Br; —CH2—CH2—X; —CH═CH2; —CH2—CH2—OH; —CH2—COOH; —CH2—OH; bCH2—OH; —COOH; —bCOOH; —O—CF(CF3)—C(O)F; —O—CF(CF3)—X; —SO2Y, wherein Y is H, F, or Cl; and —SO3H; and
        when y is 1 and z is 0, U is selected from the group consisting of divalent radicals ═CH—COOH, ═CH—CH2—OH, and ═O.
    
    


Specific examples of Formula 1A are Rf—bCF2—X, Rf—bCF2—CH2CH2X, Rf—bCF2—CH═CH2Rf—bCF2—CH2—CH2—OH, Rf—bCF2—CH2—COOH, Rf—bCF2—CH2OH, Rf—bCF2—COOH, Rf—bCF2bCOOH, Rf—bCF2—OCF(CF3)—C(O)F, Rf—bCF2—OCF(CF3)—I, Rf—bCF2—SO2—H, Rf—bCF2—SO2—Cl, Rf—bCF2—SO2—F, Rf—bCF2—SO3—H, Rf—bCF═CH—COOH, Rf—bCF═CH—CH2—OH, and Rf—bCOF.
Specific examples of Formula 1B are Rf—bCF2bCF2X, Rf—bCF2—bCF2—CH2CH2X, Rf—bCF2bCF2—CH═C H2, Rf—bCF2bCF2—CH2—CH2—OH, Rf—bCF2bCF2—CH2—COOH, Rf—bCF2—bCF2—CH2OH, Rf—bCF2bCF2—COOH, Rf—bCF2bCF2—bCOOH, Rf—bCF2bCF2—OCF(CF3)—C(O)F, Rf—bCF2bCF2—OCF(CF3)—I, Rf—bCF2bCF2—SO2—H, Rf—bCF2bCF2—SO2—Cl, Rf—bCF2bCF2—SO2—F, Rf—bCF2bCF2—SO3—H, Rf—bCF2bCF═CH—COOH, Rf—bCF2bCF═CH—CH2—OH, and Rf—bCOF.
Of particular interest are the above compounds wherein for Rf equal to Z(CmF2m)—, m is a positive integer of from 4 to 14, preferably wherein m is 6, 7, 8 and 9 and mixtures thereof. Preferred for their utility in making various derivative compounds are C6F13bCF2—I, C6F13—bCF2—COOH, C6F13—bCF2bCOOH, C7F15—bCF2—I, C7F15bCF2—SO2Cl, and C7F15bCF2 CH2CH2OH wherein b is 13 or 14.
The present invention also comprises processes for the preparation of said compounds. The processes of the present invention can also be used to prepare the corresponding unlabeled 12C-compounds.
The processes of the present invention provide convenient synthetic methods to selectively introduce 13C and 14C-carbon labels into a terminal position of the fluoroalkyl chain. If desired, the conversion sequence of Rf—X wherein X is I or Br into Rf—aCF2—X (wherein X is I or Br and a is 12, 13, or 14) is repeated to prepare the longer chain homologues CnF(2n+1)aCF2aCF2X with two added CF2 groups that are labeled or unlabelled, i.e., with an additional 12CF2, 13CF2, or 14CF2 carbon atom in the fluoroalkyl chain. The doubly labeled 13C analogs where the CnF(2n+1)13CF213CF2X materials have a molecular weight greater by two units than the corresponding unlabeled (12C) parent compounds are especially useful for unambiguous mass-specific recognition.
The processes of the invention do not use perfluorination with elemental fluorine or electrochemical fluorination, thus the synthesis can be accomplished by using ordinary laboratory equipment and glassware.
The processes of the present invention comprise a synthetic pathway that utilizes the synthesis of substituted trifluorooxirane based intermediates, preferably hexafluoropropylene oxide based intermediates. It achieves the fluorination to introduce two fluorine atoms in stepwise fashion using low reaction temperatures and mild reaction conditions. The final thermolysis yields the desired Rf—aCF2—X or Rf—bCF2bCF2X materials wherein X is Br or I and elimination of CO and CF3C(O)F. Various derivatives are prepared from the carbon labeled perfluoroalkyl halide using known reactions, thus yielding a broad array of carbon labeled compounds.
In summary, a process is provided for the preparation of a compound of

Rf—aCF(U)y(T)z  Formula 1C

wherein

    
    
        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        m is 1, 3 to 20, or a mixture thereof;
        Z is F when m is 1 and Z is selected from F, Cl, or H when m is 3 to 20 or a mixture thereof;
        a is 12, 13 or 14;
        y and z are each 1;
        U is F; and
    
    


T is —X wherein X is I or Br,
comprising


    
    
        a) contacting a perfluoroalkyl metallic compound with aCO2 to generate the corresponding acid;
        b) contacting the acid from step a) with a fluorinating agent to yield Rf—aC(O)F;
        c) contacting the Rf—aC(O)F with a substituted trifluorooxirane in the presence of a fluoride ion source to yield Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F wherein R′′ is H or F and p is 1 to 8; and
        d) contacting Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F with a metal iodide or metal bromide and heating to yield Rf—aCF(U)y(T)z.
    
    


A further process is provided for the preparation of a compound of formula 1B

Rf—bCF2bCF2 CF(U)y(T)z 

wherein

    
    
        Rf, U, T, y and z are as defined above and
        b is 13 or 14,

comprising

        a) contacting a perfluoroalkyl metallic compound of formula

(Rf)(v-w)bCF2MXw 

wherein

        Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
        M is selected from the group consisting of Zn, Li, Cd, Mg, Ca, and amalgams thereof with Hg,
        X is I or Br,
        v is the valence of M,
        w is 0 or 1, and
        b is 13 or 14,
        with CO2 to generate the corresponding acid;
        b) contacting the acid from step a) with a fluorinating agent to yield Rf—bCF2bC(O)F;
        c) contacting the Rf—bCF2bC(O)F with a substituted trifluorooxirane in the presence of a fluoride ion source to yield Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F wherein R′′ is H or F and p is 1 to 8; and
        d) contacting Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F with a metal iodide or metal bromide and heating to yield Rf—bCF2bCF(U)y(T)z.
    
    


For clarity, each stage of the synthetic process is described below with generic formulae and followed by a specific example for the preparation of compounds of Formula 1C. Analogous steps are employed for the preparation of compounds of Formula 1B using the corresponding labeled halide as a starting material.
Perfluoroalkyl metallic compounds of the formula

(Rf)(v-w)MXw or (Rf)(v-w)bCF2MXw 

wherein M is selected from the metals Ca, Li, Cd, Mg, or Zn, or amalgams thereof with mercury, v is the valency of metal M, w is 0 or 1, and Rf and X are as defined above, are prepared from Rf—X or Rf—bCF2—X respectively by convenient halogen-metal exchange reactions with organometallic reagents, by trans-metallation (metal exchange) reactions, or by direct reaction of Rf—X or Rf—bCF2—X with metals. Such organometallic reagents include for example, methyl lithium of formula R—Li, or alkyl or aryl Grignard reagents of the formula R—Mg—X wherein R is an aryl or short chain alkyl group such as C1-C4 alkyl, preferably ethyl, selected for easy removal of the byproduct R—X. In the direct reaction of Rf—X or Rf—bCF2—X with metal, suitable metals include zinc, magnesium, calcium, cadmium, and the like. This reaction is conducted in a suitable solvent, such as diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, or their combinations, which selection is dependent on the nature of (Rf)(v-w)MXw or (Rf)(v-w)bCF2MXw. These perfluoroalkyl metallic compounds are contacted with aCO2 or bCO2, which is added sequentially or is present throughout the course of the preparation of (Rf)(v-w)MXw or (Rf)(v-w)bCF2MXw to give, after hydrolysis, labeled acids Rf—aCOOH or Rf—bCF2bCOOH. aCO2 or bCO2 is prepared from commercially available sources, such as Ba13CO3 or Ba14CO3. 13CO2 is preferably prepared from Ba13CO3 by controlled addition of concentrated sulfuric acid. In a specific example, ethyl magnesium bromide is selected for easy removal of the byproduct ethyl iodide after the reaction, and to obtain satisfactory high yield of the desired product:





At from about −30° C. to about 20° C., Rf—aCOOH or Rf—bCF2bCOOH is most conveniently converted in high yield to the acid fluoride Rf—aC(O)F or Rf—bCF2bC(O)F respectively in one step by its contact with a fluorinating agent. Commercially available liquid fluorinating agents like N,N-diethylaminosulfur trifluoride (DAST) or DEOXO-FLUORTM [bis(2-methoxyethyl)aminosulfur trifluoride] are preferable for use in the laboratory for this conversion over the gaseous and toxic sulfur tetrafluoride SF4. The fluorinating agent can alternatively be N,N-dialkylaminotrifluorosulfurane, cyclohexylaminotrifluorosulfurane, cyclopentylaminotrifluorosulfurane, alkylphenylaminotrifluorosulfurane, or morpholinotrifluorosulfurane. The product obtained has a low boiling point and is easily isolated from the reaction medium by vacuum transfer. HF is generated and trapped during the vacuum transfer into a suitable trap such as a liquid nitrogen trap. In a variation of this method the acid Rf—aCOOH or Rf—bCF2bCOOH is converted into acid chloride Rf—aC(O)Cl or Rf—bCF2bC(O)Cl respectively, by the reaction with inexpensive laboratory chlorinating reagents, such as SOCl2, which is then converted into the Rf—aC(O)F or Rf—bCF2bC(O)F in a halogen exchange reaction by contacting the above N,N-diaklylaminotrifluorosulfuranes or other anhydrous inorganic fluorides, such as KF, NaF, SbF3, with the acid chloride, where complete conversion is desirable. A specific example of this reaction is:




The Rf—aC(O)F or Rf—bCF2bC(O)F is then contacted with a substituted trifluorooxirane in the presence of a fluoride ion source to yield Rf—aCF2—O—CF[(CF2)pR′′]—C(O)F or Rf—bCF2—bCF2—O—CF[(CF2)pR′′]—C(O)F, wherein R′′ is H or F and p is 1 to 8. Suitable substituted trifluorooxiranes include perfluoroalkyltrifluorooxirane or omega H-perfluoroalkyltrifluorooxirane. Examples include H(C F2)p-c-CFCF2O, and F(CF2)p-c-CFCF2O, wherein p is 1 to 8. Preferred is an n-perfluoroalkyl-1-ene oxide, such as commercially available hexafluoropropylene oxide. An example fluoride ion source is potassium fluoride. Selection of a suitable anhydrous solvent and a fluoride ion source aids in achieving the addition of only one hexafluoropropylene unit with high selectivity and high conversion. Suitable solvents include acetonitrile and glymes such as tetra(ethylene glycol)dimethyl ether (tetraglyme). A specific example of this reaction is:




The resultant Rf—aCF2[(CF2)pR′′]—C(O)F or Rf—bCF2—bCF2—O—CF[(CF2)pR′′]—C(O)F is contacted with metal iodide or metal bromide to form acid iodide or acid bromide respectively, and decarbonylated upon heating to yield Rf—aCF2—O—CF(CF3)—X or Rf—bCF2bCF2—O—CF(CF3)—X, wherein X is iodide or bromide, with the elimination of carbon monoxide. The most preferable metal iodide is lithium iodide. A specific example of this reaction is:




The Rf—aCF2—O—CF(CF3)—X or Rf—bCF2bCF2—O—CF(CF3)—above 210° C. to yield Rf—aCF2—X or Rf—bCF2bCF2—X respectively. A specific example is:




Further details of the experimental procedures are shown in the Examples.
The process of the present invention further comprises the conversion of, for instance, CnF(2n+1)X into CnF(2n+1)aCF2X, wherein X is iodide or bromide, using hexafluoropropylene oxide in synthetic methods that make available intermediate acid fluorides and secondary iodides or bromides of substituted perfluoroalkyl ethers.
The process of the present invention is used to prepare various terminal perfluoroalkyl iodides CnF(2n+1)—aCF2I or bromides CnF(2n+1)—aCF2Br starting from CnF(2n+1)—X wherein X is Br or I. Examples of 1-13C— (or 14C—) labeled 1-iodoperfluoroalkane include 1-13C-1-iodoperfluorooctane, 1-13C-1-iodoperfluoroheptane, and 1-14C-1-iodoperfluorooctane. These carbon-labeled 1-iodoperfluoroalkanes are functionalized to make a variety of labeled perfluoroalkyl derivatives including 1,2-di-13C-perfluorooctanoic acid (by the carboxylation of C6F13-13CF2—I with 13CO2), 1-iodo-1H,1H,2H,2H-3-13C (or 1-14C)-perfluorodecane (by the addition of ethylene to C7F15-13(or 14)CF2—I), and 1H,1H,2H,2H-3-13C (or 14C)-perfluorodecan-1-ol (by hydrolysis of C7F15-13(or 14)CF2—CH2CH2I) using known synthetic methods.
The above-described process of the present invention is also used to extend the perfluoroalkyl chain in CnF(2n+1)—I or CnF(2n+1)Br with CF2 groups. If used in part the method can be applied to introduce the —CF2I group or —CF2Br and to prepare perfluoroalkyl halides CnF(2n+1)—aCF2X (n=3 to 20) and their derivatives starting from other reactive intermediates such as fluorinated carboxylic acids CnF(2n+1)—aCOOH, or acid fluorides CnF(2n+1)—aC(O)F. Such carboxylic acids and acid fluorides are prepared by various methods, and then subjected to subsequent addition of one substituted trifluorooxirane unit, such as a hexafluoropropylene oxide (HFPO) unit, to such acid fluorides to obtain HFPO adducts CnF(2n+1)—aCF2OCF(CF3)C(O)F, and sequential further reactions with lithium halide to obtain secondary halides CnF(2n+1)—aCF2OCF(CF3)X, and then thermal decomposition to make primary halides CnF(2n+1)—aCF2X.
The labeled perfluoroalkyl- and highly fluorinated alkyl halides of the present invention are derivatized by various synthetic methods that have been conventionally applied to the corresponding unlabeled halides, yielding derivatives containing labeled carbon in the terminal position of the fluoroalkyl chain. A particularly useful family of products is derived from the adduct of the perfluoroalkyl iodide and ethylene to yield the 1H, 1H,2H,2H-perfluoroalkyl iodide, F(CmF2m)nbCF2CH2CH2I. 1H,1H,2H,2H-perfluoroalkyl iodide is hydrolyzed to the corresponding 1H, 1H,2H,2H-perfluoroalkanol, F(CmF2m)nbCF2CH2CH2OH, from which (meth)acrylate monomers and then fluorinated (meth)acrylate polymers are prepared. Reaction of the 1H,1H,2H,2H-perfluoroalkan-1-ol with polyisocyanates yields fluorinated polyurethane polymers. Dehydrohalogenation of 1H,1H,2H,2H-perfluoroalkyl iodide yields the terminal olefin 1H, 1H,2H-perfluoroalkene, F(CmF2m)nbCF2CH═CH2. Dehydrofluorination of 1H,1H,2H,2H-perfluoroalkan-1-ol with strong bases leads to the formation of unsaturated alcohol F(CmF2m)nbCF═CHCH2OH. Oxidation of 1H,1H,2H,2H-perfluoroalkan-1-ol yields the 2H,2H-perfluoroalkanoic acid F(CmF2m)nbCF2CH2COOH. Dehydrofluorination of the 2H,2H-perfluoroalkanoic acid yields the unsaturated acid F(CmF2m)nbCF═CHCOOH. F(CmF2m)nbCF21 subjected to deiodosulfination with sodium dithionite Na2S2O4 yields perfluoroalkyl sulfinic acid F(CmF2m)nbCF2SO2H. Perfluoroalkyl sulfinic acid F(CmF2m)nbCF2SO2H can be further chlorinated with chlorine Cl2 to form sulfonyl chloride F(CmF2m)nbCF2SO2Cl. The above sulfonyl chloride F(CmF2m)nbCF2SO2Cl is used to prepare sulfonyl fluoride F(CmF2m)nbCF2SO2F by the reaction with laboratory fluorinating agents such as DAST or metal fluorides such as KF, and converted to functional sulfonamides and their alcohol derivatives F(CmF2m)nbCF2SO2NRCH2CH2OH, wherein R′ is a short chain alkyl which are used to prepare polyurethane and (meth)acrylate polymers.
Thus, the labeled compounds of the present invention are readily derivatized into a wide range of the labeled perfluoroalkyl compounds. The 12C-analogs of these compounds are important commercial intermediates and products.
The present invention also includes a process for the preparation of a compound of formula

Rf—bCF2—bCOOH

wherein Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—, Z is F, and m is 3 to 20 or a mixture thereof, comprising contacting Rf—bCF2X wherein Rf is as defined above and X is Br or I with an organometallic compound R—Mg—X or R—Li wherein R is a C1-C4 alkyl and X is Br or I, and bCO2 to generate Rf—bCH2—bCOOH.

The iodide obtained from the process of the present invention is used to prepare several derivative compounds. For instance, the perfluoroalkyl metallic reagent, which is prepared from the labeled Rf—bCF2—X by the convenient metal exchange reactions including alkyl(or aryl) Grignard reagents, or a direct reaction of with metals (such as zinc), is contacted with bCO2, which is added sequentially or is present throughout the course of the reaction, to give, after hydrolysis, double di-1,2-bC-labeled acids Rf—bCF2—bCOOH, or, in case of using 12CO2, obtaining 2-bC-labeled acids Rf—bCF2—COOH with the carbon labeled atom as a part of perfluoroalkyl chain. A specific doubly labeled example is:




The singly labeled Rf—bCF2—COOH or the doubly labeled Rf—bCF2—bCOOH perfluoroalkyl chain acids, available by the above reaction, are further reduced by lithium aluminum hydride or by hydrogen in the presence of a catalyst to the corresponding singly labeled Rf—bCF2—CH2OH or doubly labeled alcohols Rf—bCF2—bCH2OH.
The carbon labeled compounds of the present invention are useful because such carbon labeled materials, including heavier molecular weight M+n, (n=1-5) standards, can be easily detected by mass selective spectroscopy and nuclear magnetic resonance NMR. 13C, 1H NMR, and other isotope specific analyses, as well as radioactive detection of 14C-isotope labeled molecules can detect such compounds in various reaction mixtures and biological systems. Therefore, these carbon-labeled materials are useful for a wide variety of studies including chemical and physicochemical (to determine the reactants and their products in complex chemical mixtures), kinetic studies, toxicological (pharmacokinetics, microsome and hepatocyte metabolism) environmental fate (biodegradation under aerobic and anaerobic conditions) and others. The processes of the present invention are useful to prepare various carbon-labeled compounds or to selectively introduce labeled carbons at desired positions.
Materials
1. Ethyl Magnesium bromide, acetonitrile, anhydrous potassium fluoride, and DEOXO-FLUOR (bis(2-methoxyethyl)aminosulfur trifluoride) are available from Aldrich, Milwaukee Wis.
2. n-C6F13—I and hexafluoropropylene oxide (HFPO) is available from Lancaster, Windham, N.H.
3. DAST (N,N-Diethylamino sulfur trifluoride) is available from Aldrich, Milwaukee Wis. or SynQuest Laboratories, Inc., Alachua, Fla.
4. VERTREL-XF (2H,3H-Perfluoropentane) is available from Oakwood Products, Inc.(Fluorochem USA) West Columbia, S.C.
5. Ba13CO3 (98% 13C) and CD2=CD2 is available from ISOTEC, Inc. Miamisburg, Ohio.
6. Ba14CO3 is available from SIGMA, St. Louis, Mo.
EXAMPLES
The examples provided below demonstrate the key steps of the technology, and are not intended to limit the scope of the present invention. The procedures of the examples are also applicable to unlabeled (12C) compositions and labeled 14C compositions.
Example 1
C6F13-Grignard reagent was prepared under nitrogen from commercially available C6F13I (83.6 g) in anhydrous ether 1.1 L, by the addition of EtMgBr 70 mL (3M sol. in ether), at −62-70° C., reacted for 40 min, and cooled to −95° C. 375 mL of THF were added. 13CO2, generated from Ba13CO3 (28.3 g) by the addition of concentrated H2SO4, was introduced into the reaction, which was gradually warmed to −70-78° C., stirred for 5-6 hours and then slowly warmed to room temperature (overnight). 10 mL of water were added and the solvent was distilled off at ambient pressure (<100° C. in the reaction vessel) following by brief application of vacuum (30 Torr, 4 kPa). Aqueous sodium hydroxide solution (5%) was added and the crude material was washed with pentane. The aqueous layer was treated with H2SO4 (to obtain a resulting 20% H2SO4 solution). The crude acid C6F13—13COOH (62.7 g) was separated as the bottom layer and further distilled in vacuum.
Conversion of C6F13—13COOH (132.4 g, prepared as described above) into acid fluoride C6F13—13C(O)F was made by slowly adding DAST (91.5 g, 1.5 eq.) at −30 to 20° C. (exotherm), followed by transfer of the product (104.2 g) in vacuum (20° C./5-10 Torr, 0.67-1.3 kPa). Caution: HF, generated during the reaction, was trapped during the vacuum transfer into the liquid nitrogen trap.
A 4-neck 250-mL flask, equipped with magnetic stirring, dry-ice cooled condenser, thermocouple, and inlet tube, was charged with 1-13C perfluoroheptanoic acid fluoride (C6F13—13C(O)F, 103.5 g, prepared as described above), dry potassium fluoride (4.0 g), and acetonitrile (4.3 g). Hexafluoropropene oxide (HFPO, 69.5 g, 1.5 eq. overall) was slowly introduced into the flask over a period of 16 hours, maintaining the reaction temperature in the range 24-40° C. HFPO refluxed during this addition, and a 40-60° C. warm-water bath was used to maintain the temperature. The reaction provided 1:1-HFPO adduct C6F13—13CF2OCF(CF3)C(O)F with high selectivity and greater than 95% conversion (GC/MS). The product C6F13—13CF2OCF(CF3)C(O)F was transferred in vacuum to obtain 134.82 g of crude product (pot temperature 30-56° C.) at 24 Torr (3.2 kPa). A small top layer of distillate, primarily acetonitrile (7.6 g), was decanted.
1:1-HFPO adduct (C6F13—13CF2OCF(CF3)C(O)F, 127.0 g, prepared as described above was reacted at 164-168° C. (reflux) overnight with dry lithium iodide (42.0 g) to obtain the secondary iodide C6F13—13CF2OCF(CF3)I. A foreshot of volatile materials that distilled at the beginning of the reaction (161-172° C., b.p.=90-132° C.) was rejected. The gasses were scrubbed using aqueous sodium hydroxide. The crude product was distilled under vacuum (96.5 g, 66° C./30 Torr (4.0 kPa) to 54° C./5 Torr (0.67 kPa)). Iodine was separated at the bottom of the flask to obtain clear dark pink liquid.
Crude secondary iodide (C6F1313CF2OCF(CF3)I, 93 g, prepared as described above) was heated at 235-240° C. for 4-6 h in a closed system. The container was cooled to 0-25° C. and carefully opened to evaporate the CF3C(O)F byproduct (scrubbing the gases using aqueous sodium hydroxide solution). 74.8 g of product C6F13—13CF2I (a light pink liquid, overall 76.0 g) were purified by vacuum distillation on 10-plate column to obtain C6F1313CF2I (33.0 g 68° C./67 Torr (8.9 kPa)) with 99.1-99.7% purity, established by GC/MS.
Example 2
C6F13—13CF2—I (31.5 g) (prepared as in Example 1 above) was carboxylated with 13CO2 (12.0 g of Ba13CO3) using the procedure of Example 1. The resulting crude acid C6F13—13CF213COOH (22.8 g) was distilled in vacuum. A first fraction of 1.36 g was rejected. The second fraction (21.3 g, 77-83° C./3 Torr, 0.4 kPa) was further crystallized by double recrystallization from small amount of VERTREL-XF to obtain 99.5% pure C6F13—13CF213COOH(1H, 19F NMR and GC/MS).
Example 3
C7F15I (32.3 g) was reacted with EtMgBr (22.5 mL of 3M sol. in ether) and 13CO2 generated from Ba13CO3 (10.0 g) as described in Example 1. Crude C7F1513COOH acid was crystallized from 1,1,2-trichlorotrifluoroethane to obtain 13.2 g of purified product.
C7F1513COOH (41.6 g), prepared as described above, was reacted with DEOXO-FLUOR (29.4 g) at −30 to 20° C. (exotherm). The product C7F1513C(O)F (38.4 g) was transferred in vacuum at (15-20° C./5-10 Torr).
C7F1513C(O)F (59.5 g), prepared as described above, KF (4.2 g), acetonitrile (4.8 g) was reacted with hexafluoropropylene oxide (HFPO) (67 g) over 16 hours as described in Example 1. The product C7F1513CF2OCF(CF3)C(O)F (72 g) was distilled in vacuum from warm water bath (60° C./1 Torr).
C7F1513CF2OCF(CF3)C(O)F (118.8 g), prepared as described above, was stirred and heated at 164-175° C. with lithium iodide (38.1 g) overnight. The product was distilled in vacuum to obtain 93.3 g of C7F1513CF2OCF(CF3)I.
C7F1513CF2OCF(CF3)I (13.8 g) was evacuated and heated to 220-250° C. for 2.5 hours in closed 250 mL glass flask equipped with TEFLON stopper. After cooling (−10-0° C.) the flask was carefully opened and slowly warmed to evaporate the CF3C(O)F (scrubbed by aqueous sodium hydroxide solution). 11.8 g of crude product C6F13-13CF2I were obtained, and further purified by fractional distillation in vacuum on 10 plate column to obtain C7F1513CF2I (94° C./21 Torr, purity 98% GC/MS).
Example 4
C7F15—13CF2I (18.5 g, 33.8 mmol) was charged into a 100-mL stainless steel autoclave, closed and evacuated. Ethylene-d4 CD2=CD2 (small excess) was charged into the container in two portions, heated and reacted at 200° C./pressure 30-67 psi for 6.5 hours. The reaction mass was cooled, and the excess of ethylene vented off to obtain C7F1513CF2CD2-CD2I (17.0 g, 29.6 mmol, yield 87.5%), which was used for further reaction without additional purification.
Example 5
C8F1713CF2CH2CH2I (16 g, 26.4 mmol) 4 mL of water and 44 g of N,N-dimethylformamide were reacted at 125° C. for 30 hours. When the conversion of C8F1713CF2CH2CH2I was complete (GC), hot deionized water (28 mL) 45° C. was added. Maintaining the temperature at 40-60° C., the product was extracted with VERTREL-XF and diethyl ether, and washed with water. Solvent was removed in vacuum to obtain 14.0 g of crude material, containing 20% (GC) of C7F15—13CF2—CD=CD2. It was further distilled and purified by column chromatography on silicagel (60-200 mesh) to isolate 11.0 g of C7F5 13CF2CD2CD2-OH (96% pure, GC/FID) from the fractions enriched in C7F15—13CF2—C2H═C2H2.
Example 6
Perfluoroheptyl Iodide (12.65 g, 25 mmol) in ether (100 mL) was cooled to −50° C. and reacted with 3M solution of ethylmagnesium bromide in ether for 1 h. The reaction mixture was cooled in liquid nitrogen bath, tetrahydrofuran (100 mL) added, and carbon dioxide [14C](1400 mCi, 24 mmol) added by condensing in vacuum. The reaction flask was warmed to −78° C. (over 4 h), and then warmed to room temperature overnight. The reaction mixture was quenched with 6N sulfuric acid at −30° C. and most of the organic solvents removed. The aqueous layer was adjusted to pH 11 with 25% sodium hydroxide, washed with pentane, and acidified to pH 1 with 6N hydrochloric acid. The aqueous layer was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under vacuum (60° C./1 Torr) to obtain 1-14C-perfluorooctanoic acid (1100 mCi, 19 mmol).
1-14C-Perfluorooctanoic acid (1100 mCi, 19 mmol), prepared as above, was vacuum transferred into a flask containing DEOXOFLUOR (8.436 g, 38 mmol) cooled in liquid nitrogen bath. The flask was allowed to warm to room temperature and the product was distilled under vacuum (20° C./1 Torr) to obtain 1-14C-perfluorooctanoyl fluoride (3.5 mL,  ̃14 mmol).
A mixture of anhydrous potassium fluoride (0.33 g, 5.7 mmol), tetraglyme (4.0 mL), hexafluoropropylene oxide (HFPO) (1215 mL, 48 mmol), and 1-14C-perfluorooctanoyl fluoride (3.5 mL,  ̃14 mmol) was heated at 60° C. under vacuum ( ̃1 mm) for 36 h. The product was distilled under vacuum (60° C./1 Torr) and collected at −78° C.
A mixture of C7F1514CF2OCF(CF3)C(O)F ( ̃14 mmol) and lithium iodide (3.72 g, 28 mmol) was heated at 90° C. under vacuum ( ̃1 mm) for 3 h. The product (C7F1514CF2OCF(CF3)C(O)I, 4.2 mL) was distilled in vacuum (60° C./1 Torr) and collected at −20° C.
C7F514CF2OCF(CF3)C(O)I (4.2 mL), prepared as above, was evacuated, closed and heated at 215° C. for 16 h. The product was distilled under vacuum (20° C./1 Torr) and trapped at −20° C. to obtain 1-14C perfluorooctyl iodide (1.7 mL), which was used to obtain further derivatives.
Example 7
1-14C-perfluorooctyl Iodide (1.7 mL, 1.4 g, 6.2 mmol), as prepared in Example 6, and 1,1,2-trichlorotrifluoroethane (0.5 mL), were charged into a steel vessel (capacity 35 mL). The ethylene was added (372 mL, 14.88 mmol) and the mixture was heated at 200° C. for 15 h. The reaction mixture was transferred under vacuum (1 mmHg) at 80° C., and 1-iodo-3-14C-1H, 1H,2H,2H-perfluorodecane (200 mCi, 3.4 mmol) was collected at −20° C.
Example 8
A mixture of 1-iodo-3-14C-1H,1H,2H,2H-perfluorodecane (200 mCi, 3.4 mmol), prepared as in Example 7, N,N-dimethylformamide (9 mL), and water (0.9 mL) were heated at 120° C. for 20 h. The reaction mixture was diluted with water (50 mL) and extracted with ether. The ether layer was concentrated at about 20 mmHg. The residue was dissolved in 1,1,2-trichlorotrifluoroethane and purified by column chromatography (silica gel, pentane/ether, 3/1, 600 mL). Fractions containing product were combined and concentrated. The residue (57 mCi) was further purified by distillation under vacuum (about 1 mm Hg) at 80° C. and 3-14C-1H,1H,2H,2H-perfluorodecan-1-ol was collected at −20° C. (54 mCi, 460 mg). Radiochemical purity: greater than 98.16%, specific activity (weight assay) 54.3 mCi/mmol. Structure confirmed by 1H and 19F NMR (CDCl3).

## Claims

1. A compound having the formula


Rf—bCF(U)y(T)z  Formula 1A or



Rf—bCF2bCF(U)y(T)z  Formula 1B


wherein
Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
m is 1, 3 to 20, or a mixture thereof;
Z is F when m is 1, and Z is F, Cl, or H when m is 3 to 20, or a mixture thereof;
b is 13 or 14;
y is 1 and z is 0 or 1; and
when y and z are each 1, U is F, and T is selected from the group consisting of monovalent radicals —X wherein X is I or Br, —CH2—CH2—X, —CH═CH2, —CH2—CH2—OH, —CH2—COOH, —CH2OH, —bCH2OH, —COOH, —bCOOH, —O—CF(CF3)—C(O)F, —O—CF(CF3)—X, —SO2Y wherein Y is H, F or Cl, and —SO3H; and
when y is 1, and z is 0, U is selected from the group consisting of divalent radicals ═CH—COOH, ═CH—CH2—OH, and ═O.

2. A compound of claim 1 wherein m is a positive integer equal to 6, 7, 8 or 9.

3. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is I or Br.

4. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is CH2—CH2—X wherein X is I or Br.

5. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is bCOOH.

6. A compound of claim 5 wherein m is 6 and b is 13.

7. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is bCH2OH.

8. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is —CH═CH2.

9. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is —CH2—CH2—OH.

10. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is —CH2OH.

11. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is —O—CF(CF3)—C(O)F.

12. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is —O—CF(CF3)—I.

13. A compound of claim 1 wherein y and z are each 1; Z and U are each F; and T is —SO3H or —SO2Y wherein Y is H, F or Cl.

14. A compound of claim 1 wherein y is 1, z is 0, and U is ═CH—COOH.

15. A compound of claim 1 wherein y is 1, z is 0, and U is ═CH—CH2—OH.

16. A compound of claim 1 wherein y is 1, z is 0, and U is ═O.

17. A process for the preparation of


Rf—bCF2bCF(U)y(T)z  Formula 1B


wherein
Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
m is 1, 3 to 20, or a mixture thereof;
Z is F when m is 1 and Z is selected from F, Cl, or H when m is 3 to 20 or a mixture thereof;
b is 13 or 14;
y and z are each 1;
U is F; and
T is —X wherein X is I or Br,

comprising
a) contacting a perfluoroalkyl metallic compound of formula


(Rf)(v-w)bCF2MXw 



wherein
Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—,
M is selected from the group consisting of Zn, Li, Cd, Mg, Ca, and amalgams thereof with Hg,
X is I or Br,
v is the valence of M,
w is 0 or 1, and
b is 13 or 14,
with CO2 to generate the corresponding acid;
b) contacting the acid from step a) with a fluorinating agent to yield Rf—bCF2bC(O)F;
c) contacting the Rf—bCF2bC(O)F with a substituted trifluorooxirane in the presence of a fluoride ion source to yield Rf—bCF2—bCF2—O—CF[(CF2)pR′′]—C(O)F wherein R′′ is H or F and p is 1 to 8; and
d) contacting Rf—bCF2—bCF2—O—CF[(CF2)pR′′]—C(O)F with a metal iodide or metal bromide and heating to yield Rf—bCF2bCF(U)y(T)z.

18. The process of claim 17 wherein (Rf)(v-w)bCF2MXw is prepared by contacting Rf—bCF2X with a Grignard reagent.

19. The process of claim 17 wherein the fluorinating agent is selected from the group consisting of N,N-diethylaminosulfur trifluoride, [bis(2-methoxyethyl)aminosulfur trifluoride], sulfur tetrafluoride, dialkylaminotrifluorosulfurane, cyclohexylaminotrifluorosulfurane, cyclopentylaminotrifluorosulfurane, alkylphenylaminotrifluorosulfurane, and morpholinotrifluorosulfurane.

20. The process of claim 17 further comprising contacting the acid from step a) with a halogenating agent to yield an acid halide prior to contacting with the fluorinating agent.

21. The process of claim 19 wherein the fluorinating agent is selected from the group consisting of KF, NaF, SbF3, N,N-diethylaminosulfur trifluoride, [bis(2-methoxyethyl)aminosulfur trifluoride], sulfur tetrafluoride, dialkylaminotrifluorosulfurane, cyclohexylaminotrifluorosulfurane, cyclopentylaminotrifluorosulfurane, alkylphenylaminotrifluorosulfurane, and morpholinotrifluorosulfurane.

22. The process of claim 17 wherein the substituted trifluorooxirane is hexafluoropropylene oxide.

23. The process of claim 17 wherein the fluoride ion source is KF or CsF.

24. The process of claim 17 wherein metal iodide is lithium iodide.

25. A process for the preparation of a compound of formula


Rf—bCF2—bCOOH


wherein Rf is a linear or branched perfluoroalkyl radical Z(CmF2m)—, Z is F, and m is 3 to 20 or a mixture thereof, comprising contacting Rf—bCF2X wherein Rf is as defined above and X is Br or I with an organometallic compound R—Mg—X or R—Li wherein R is a C1-C4 alkyl and X is Br or I, and bCO2 to generate Rf—bCH2—bCOOH b is 13 or 14.