Organic Compounds Containing Fluorine

CHAPTER 4

Organic Compounds Containing Fluorine

B Y PAUL T A R R A N T

Department of Chemistry, University of Florida, Gainsville, Florida Page

Introduction 213 Hydrofluorocarbons 214

Aliphatic Hydrofluorocarbons 214 Aromatic Compounds with an Aliphatic Side Chain 220

Compounds with Fluorine in an Aromatic Nucleus 223

Unsaturated Hydrofluorocarbons 224

Cyclobutane Derivatives 226

Alcohols 229 Ethers 232 Aldehydes and Ketones 235

Acids and Their Derivatives 238

Amines 242 Heterocyclic Compounds 243

Amino Acids 246 Dyes 248 Drugs 253 Pesticides 258 Polymers Containing Fluorine 260

Styrene Derivatives 261 Acrylic Acid and Its Derivatives 264

Vinyl Fluoride 265 1-Chloro-l-fluoroethylene 266

Vinylidene Fluoride 267 Trifluoroethylene 267 Chlorotrifluoroethylene 267

Fluoroprene 269 2,3-Difluoro- and 2-Chloro-3-fluorobutadiene 270

Bibliography

3 0

8

Introduction

Organic compounds containing fluorine have held the attention of chemists for a long time because of the unusual and often unexpected properties which the fluorine atom gives to the molecule. For example, monofluoro compounds are sometimes very unstable, and certain com­

pounds such as the fluoroacetates are quite reactive physiologically; on the other hand, other compounds such as CF ₃ CH ₂ C1 are quite unreactive both chemically and physiologically.

213

214 PAUL TARRANT

The introduction of fluorine atoms into an organic molecule makes pronounced changes in the physical properties of the compounds as well.

Many chemists have been surprised to find the index of refraction of many fairly common fluorine compounds to be less than 1.3000, the lowest reading on the ordinary refractometer. Although the replacement of hydrogen by fluorine in a hydrocarbon usually gives a negligible change in boiling point, marked changes often occur in molecules containing functional groups.

The following data show the change in boiling points as fluorine atoms are progressively introduced into ethyl acetate :

The organic chemists arc continuously striving to tailor-make new molecules with unusual properties, and fluorine compounds are being used in increasingly large amounts in synthetic work. It may be a while before the chemist can obtain a wide variety of compounds with func­

tional groups, but there are available today certain reactive fluorine compounds which can be used in synthetic processes. For example, a number of olefins such as C F ₂ = C H ₂ , C F ₂ = C F C 1 , and C F ₂ = C C 1 ₂ can be obtained in pound batches; these molecules react readily with alcohols, amines, mercaptans, and with themselves to give other compounds con­

taining the ordinary functional groups such as ether, amide, sulfide, etc.

A vast number of compounds can also be obtained from the fluorocarbon derivatives such as the acids, aldehydes, etc., as discussed in Volume I.

It is hoped that the following pages will reveal to the reader the variety of interests which has led a great many investigators to contribute so much to our knowledge of the chemistry of fluorine compounds; the workers in this field may feel justly proud of their accomplishments. It is also hoped that the uninitiated may see the need for additional research in this area and accept*the challenge it offers.

In general, the methods most frequently employed for the preparation of aliphatic hydrofluorocarbons are: (a) the addition of hydrogen fluoride to an unsaturated compound, or (6) the replacement of other halogens by the use of a suitable fluorinating agent such as antimony trifluoride, mercuric fluoride, hydrogen fluoride, or even potassium fluoride.

C H 3 C O 2 C 2 H 6

C H 2 ^{F C 0} 2 ^C 2 ^H 6

C H F

2 ^{C 0} 2 ^C 2 ^{H 6}

C F 3 ^{C 0} 2 ^{C > H} 5

77°C 116°

99°

62°

Hydrofluorocarbons

ALIPHATIC HYDROFLUOROCARBONS

ORGANIC COMPOUNDS CONTAINING FLUORINE 215 The preparation of ethyl fluoride can be carried out conveniently and in good yields simply by heating ethylene and hydrogen fluoride for several hours in an autoclave (156). Other olefins such as propylene and cyclohexene react readily to give the corresponding alkyl fluoride. How­

ever, it should be pointed out that alkyl fluorides are generally quite difficult to purify sufficiently to prevent their decomposition except for the low boiling compounds. Traces of water or acids or even the use of temperatures of 60 to 75° during a distillation will often cause the molecule to lose hydrogen fluoride and form olefins which may undergo polymeriza­

tion. This possibility is particularly noticeable in the case of secondary or tertiary fluorides.

C H 3 C H 3

I I C H ₃ — C — C H ₃ > C H ₂ = C — C H ₃ + H F

I

F C H ₃

I H F

n C H ₂ = C — C H ₃ > [—CH ₂ —C(CH ₃ ) ₂ —] _n

The preparation of alkyl fluorides by the reaction of alcohols and hydrogen fluoride appears attractive but such is actually not the case.

In the first place, any water formed in the reaction will remove hydrogen fluoride from the alkyl fluoride formed to give the olefin. Even if the olefin did not polymerize in the presence of the acid, it is possible that a new alkyl fluoride will be formed by the reaction of hydrogen fluoride with the olefin. Since hydrogen fluoride adds to olefins in the normal manner, secondary or tertiary fluorides are formed. Therefore, it can readily be seen that the reaction of primary alcohols may give rise to a mixture of primary and secondary alkyl fluorides.

1. R C H ₂ C H ₂ O H + H F - > R C H ₂ C H ₂ F + H ₂ 0

H 2 ⁰

2. R C H ₂ C H ₂ F > R C H = C H ₂ + H F 3. R C H = C H ₂ + H F - + R C H F C H ₃

Because of the unavoidable difficulties in the preparation of monofluorides in addition to their limited usefulness due to their instability, the litera­

ture contains few references to them.

Certain difluoroalkanes can be made in excellent yields by adding hydrogen fluoride to an olefin containing a chlorine atom on one of the carbon atoms of the unsaturated bond. The reaction proceeds so readily to give the difluoro compound that care must be exercised to prevent an excess of hydrogen fluoride in reactions in which the chlorofluoro deriva­

tive is desired. For example, in the reaction between 2-chloro-2-butene and

216 PAUL TARRANT

hydrogen fluoride, even a slight excess of the latter gives a considerable amount of 2,2-difluorobutane together with some 2,2-dichlorobutane.

The reactions with chloroolefins in many cases take place at room tem­

perature or below and thus the tar usually formed in many fluorination reactions is absent; furthermore, since a large excess of hydrogen fluoride is unnecessary for the reaction, elaborate equipment for separating the unreacted fluorinating agent is not required.

Renoll has reported the addition of hydrogen fluoride to several 2-chloro-2-alkene compounds to give 2,2-difluoroalkanes in yields from 60 to 70% (393). Under the conditions employed, with an excess of hydrogen fluoride, only the substitution product was ever isolated.

Henne and Pleuddeman made an extensive study of the addition of hydrogen fluoride to haloolefins (201). Olefins of the type R H C = C H X did not react well to yield one or two simple products. For example, C H ₃ C H = C H C 1 gave traces of C ₂ H ₅ C H F ₂ , 5 % of unreacted olefin, 10%

of the addition product, 20% of CH ₃ CHC1CH ₂ C1, and the rest tar. On the other hand, monochloroolefins of the type R R ' C = C H C 1 reacted smoothly with hydrogen fluoride at low temperature to give excellent yields of the simple addition product. From ( C H ₃ ) ₂ C = C H C 1 at —23°, there was obtained a 6 5 % yield of (CH ₃ ) ₂ CHCHFC1; tar formation was negligible at this temperature.

As might be expected, compounds of the type R R O = C C 1 ₂ also reacted smoothly at 65° to give both the addition product and more highly fluorinated compounds.

Dihaloolefins of the type R C X = C R ' X varied considerably in their reactivity toward hydrogen fluoride. Neither CHC1=CHC1 nor CHC1=CC1 ₂ was found to react with hydrogen fluoride even under drastic conditions. Although CH ₃ CC1=CHC1 reacted smoothly at 120°

with hydrogen fluoride, low yields of fluoro compounds were obtained.

However, in the presence of boron trifluoride, even perhaloethylenes can be made to accept hydrogen fluoride (183). Tetra-, tri-, and 1,2-di- chloroethylene gave the corresponding addition products in yields of 30, 60, and 26%, respectively; even the very unreactive C F C l ^ C F C l gave a 4 3 % yield of CHFC1CF ₂ C1.

The addition of hydrogen fluoride to acetylenic hydrocarbons has received a great deal of attention. This reaction is of interest in the preparation of compounds on an industrial scale because of its simplicity and its complete utilization of the fluorinating agent. It is possible to add a single molecule of hydrogen fluoride to the triple bond to give vinyl fluoride, and, in certain cases, fluoroprene is obtained as a by-product.

If two molecules of hydrogen fluoride add, then the saturated 1,1-difluoro-

ethane results. It is believed that this is the initial step in the process

ORGANIC COMPOUNDS CONTAINING FLUORINE 217 used by a leading American industrial concern for the preparation of a variety of 1,1-difluoroethanes such as CH ₂ C1CHF ₂ , CH ₃ CF ₂ C1, and more highly chlorinated products.

The addition of hydrogen fluoride to acetylene was apparently first carried out in the middle 1930's in Germany (243, 248). In recent years, in the United States and in England, the reaction has been studied as a method of preparation of vinyl fluoride, 1,1-difluoroethane, and 2-fluoro- butadiene-1,3. In some cases mercury salts are listed as catalysts, whereas in others fluorosulfonic acid, boron fluoride, and hydrogen chloride are claimed to have catalytic properties.

Calfee and Bratton claim the complete conversion of acetylene to C H ₃ C H F ₂ by passing C ₂ H ₂ and hydrogen fluoride in a molar ratio of 1:2 into a mixture of fluorosulfonic acid and hydrogen fluoride maintained at 0°. At higher temperatures both vinyl fluoride and the saturated difluoride are obtained (57).

Hillyea claims that good yields of vinyl fluoride are obtained by pass­

ing acetylene, hydrogen chloride, and hydrogen fluoride over mercuric chloride maintained at 100 to 315°; in the absence of hydrogen chloride, the yields of vinyl fluoride were low (219).

Aluminum oxide or fluoride is used as the catalyst in a process de­

scribed by Hillyea and Wilson for the production of vinyl fluoride or difluoroalkanes (220). Acetylene and hydrogen fluoride in a molar ratio of 1:2.24 at 315° give vinyl fluoride and C H ₂ F C H ₂ F . 1-Hexyne gives an 8 5 % yield of C H ₃ ( C H ₂ ) ₃ C F ₂ C H ₃ , and 1-pentyne gives an 8 4 % yield of C H ₃ ( C H ₂ ) ₂ C F ₂ C H ₃ under similar conditions. The catalytic activity of the aluminum compounds did not decrease over periods as long as 32 hours.

Mercuric acetate or oxides as well as zinc- or nickel-mercury chromite have been impregnated on charcoal for use as catalysts in the reaction (254, 255). It has been claimed that mercury compounds deposited on alkaline earth metal salts serve as better catalysts because charcoal reduces and deactivates the mercuric salts at elevated temperatures.

In the past several years some interest has been shown in elastomers

made from fluoroprene, C H ₂ = C F C H = = C H ₂ , because of their oil and

sunlight resistance, high resilience, and other desirable qualities. The

monomer can be made by several methods, but a number of patents have

been issued to cover the reaction of vinylacetylene with hydrogen fluoride

(72, 418, 419). In a typical example, hydrogen fluoride, vinylacetylene,

and nitrogen are passed over a charcoal-supported mercuric salt catalyst

at 40° with a contact time of about 40 seconds. The conversion to

fluoroprene was about 4 0 % ; in addition, some 3,3-difluoro-l-butene was

obtained.

218 PAUL TARRANT

Aliphatic hydrofluorocarbons are frequently obtained by replacing another halogen atom with fluorine by the use of a suitable fluorinating agent. In most cases, organic chlorine compounds are generally used as starting materials and very often products containing both fluorine and chlorine are obtained. Since the methods of replacement of chlorine in such aliphatic compounds has been discussed quite adequately by Park

(Chapter 15, Volume I), only a very brief account will be given here.

Actually, the number of saturated aliphatic compounds containing only hydrogen and fluorine which have been obtained by this method is limited. Probably the best known is 1,1,1-trifluoroethane, C H 3 C F 3 ,

which can be prepared in excellent yield by heating methyl chloroform with anhydrous hydrogen fluoride (425). Sometimes antimony trifluoride with a pentavalent antimony salt as catalyst is used; C H 3 C H 2 C C I 3 has been converted to C H ₃ C H ₂ C F ₃ by such a mixture. A somewhat more convenient procedure is to carry out a simultaneous addition across a double bond and replacement of chlorine atoms in the molecule; for example, by such a reaction C H ₃ C F ₃ can be obtained readily from C H ₂ = C C 1 ₂ and C ₂ H ₅ C F ₃ from C H ₃ C H = C C 1 ₂ .

It is also reasonably easy to effect the replacement of both chlorine atoms in compounds of the type RCC1 ₂ R/ by refluxing such compounds with antimony trifluoride and a suitable catalyst. Whalley has reported that stannic chloride is superior to antimony pentachloride as a catalyst in such reactions since the formation of tars is greatly reduced (545, 546).

Although detailed directions for fluorination reactions are often found in the literature, quite frequently the experimenter meets with little success in carrying out the same or similar reactions for the first several trials until certain details such as rate of heating, amount of catalyst, and speed of stirring, which may seem insignificant, are worked out properly.

Mercuric fluoride has been found to be an effective reagent for replac­

ing other halogen atoms to yield aliphatic fluoro compounds (193). How­

ever, it is expensive and its preparation requires the use of elemental fluorine. In 1938, Henne reported that excellent results could be obtained by employing a mixture of mercuric oxide and hydrogen fluoride as the active fluorinating agent (179). By the use of such a reagent, the replace­

ment of chlorine can be carried out at low temperatures where the forma­

tion of by-products and tars are minimized and, consequently, good yields of the desired product are often obtained. For example, 70 to 80% yields of compounds such as C H ₂ F ₂ and C H ₃ C H F ₂ have been obtained.

In some cases, mercurous fluoride, which is easily prepared, is treated

with a second halogen to give a mixture of mercuric fluoride and mercuric

halide which then converts organic halogen compounds to fluorides. For

ORGANIC COMPOUNDS CONTAINING FLUORINE 219 instance, methylene fluoride has been obtained from methylene iodide, mercurous fluoride, and iodine (38).

In recent years, potassium fluoride has been used to replace other halogen atoms for the preparation of alkyl fluorides. For example, Gryskiewicz-Trochimowski has reported that C 6 ^{H i} 3 ^{F and} C 1 1 H 2 3 F have been obtained in 20% yields from the corresponding chlorine analogs (159). Hoffmann (231) has improved the process for preparing aliphatic fluorides by carrying out the reaction with solvents such as the simple glycols; for example, by using this technique the yield of hexyl fluoride has been increased to 54%.

Although this method is inferior in some respects to those using antimony or mercury fluorides, the availability of potassium fluoride and the ease with which the reaction can be carried out in conventional equipment make it a convenient method in certain instances. Surprisingly enough, sodium fluoride does not participate in exchange reactions of this type.

Alkyl fluorides are reported to lose hydrogen fluoride readily. How­

ever, compounds containing two fluorine atoms on a single carbon are remarkably stable. For instance, McBee and Hausch were unable to effect the removal of hydrogen fluoride from C H 3 ^{C F} 2 C H = C H 2 even on heating with potassium hydroxide at 200° (326).

It is well recognized that the presence of two or more fluorine atoms on a terminal carbon with a second halogen reduces the reactivity of the halogen. Numerous instances have also shown that the — C F 2 ^{— or the} C F 3 — group also greatly retards the reactivity of a halogen atom on an adjacent carbon. For example, C F 3 ^{C H} 2 B r has not as yet been made into a Grignard reagent and does not substitute readily with bases to give either an alcohol or an ether. The — C F 2 — group likewise stabilizes a chlorine atom next to it since the dehydrochlorination of C H 3 ^{C F} 2 ^- CHC1CH 3 occurs only slowly with alcoholic potassium hydroxide even at 150° (326). In contrast, Henne and Hinkamp have shown that C H 3 ^{C F} 2 ^- CH 2 ^CH 2 C1 gives the olefin readily at a much lower temperature (188).

It is postulated in the latter case that the hydrogen atom alpha to the

— C F 2 — group is more acidic and is therefore removed by alkali, following

which the chloride ion is eliminated and the olefin formed. In some cases,

the reactivity of a chlorine atom is so greatly reduced that it seems that a

fluorine atom from a methforyl group is displaced. For example, McBee

and Bolt have shown that CF 3 ^CHC1CF 3 reacts with sodium aryl oxides to

give compounds of the type CF 3 ^CHC1CF 2 0R rather than the expected

C F 3 ^{C H ( C F} 3 ) O R (316). However, in this case, the hydrogen atom is

probably very susceptible to attack and, when removed, causes a fluoride

220 PAUL TARRANT

ion to be eliminated to form the olefin CF 3 CC1=CF2, which accepts the phenol to form the ether CF 3 ^CHC1CF 2 ^0R.

The chlorination of hydrofluorocarbons has been the subject of several investigations. Henne has amply demonstrated that the chlorination of compounds containing two or three fluorine atoms per carbon follows certain definite patterns. For instance, the chlorination of C F 3 ^{C H} 2 ^{C H} 3 ⁱⁿ sunlight gave successively CF 3 ^CH 2 ^CH 2 ^{C1, CF} 3 ^CH 2 ^CHC1 2 ^{, C F} 3 ^{C H} 2 ^{C C 1} 3 and then proceeded directly to CF 3 ^CC1 2 ^CC1 3 without any tetrachloride being found (213). Again the resistance to substitution of hydrogen atoms alpha to a methforyl group was demonstrated in the chlorination of C F 3 ^{C H} 2 ^{C H} 2 ^{C H} 3 , which gave only C F 3 ^{C H} 2 ^{C H} 2 ^{C H} 2 C 1 and C F 3 ^{C H} 2 ^- CHC1CH 3 (189). Chlorine more often will accumulate on a carbon atom already holding chlorine as shown when CF 3 ^CH 2 ^CHC1CH 3 gave 4 parts of C F 3 ^{C H} 2 ^{C C 1} 2 ^{C H} 3 to 3 of CF 3 ^CH 2 ^CHC1CH 2 C1 and when C F 3 ^{C H} 2 ^{C H} 2 ^- CH 2 C1 gave twice as much C F 3 ^{C H} 2 ^{C H} 2 ^{C H C 1} 2 ^{as CF} 3 ^CH 2 ^CHC1CH 2 ^C1.

In sunlight and in the presence of water C H 3 ^{C F} 2 ^{C H} 2 ^{C H} 3 ^upon chlorination gave 2 parts of CH 3 ^CF 2 ^CHC1CH 3 and 3 parts of C H 3 ^{C F} 2 ^- CH 2 ^CH 2 C1 but no C H 2 ^{C 1 C F} 2 ^{C H} 2 ^{C H} 3 (188). The methyl group adjacent to the C F 2 was not attacked even when three chlorine atoms entered the butane molecule, again indicating the reluctance of certain hydrogen atoms to take part in substitution reactions with chlorine.

Quite probably higher chlorination temperatures give a more random distribution of chlorine atom since McBee and Hausch found a consider­

ably greater amount of CH 3 ^CF 2 ^CHC1CH 3 than was previously reported when C H 3 ^{C F} 2 ^{C H} 2 ^{C H} 3 was chlorinated (326). A — CC1F— group is much less effective in directing substitutive chlorination away from the alpha position than — C F 2 — or — C F 3 groups. For example, the chlorination of CH 3 ^CFC1CH 2 ^CH 3 yielded 4 5 % CH 3 ^CFC1CHC1CH 3 as against 2 1 % CH 3 ^CFC1CH 2 ^CH 2 ^C1.

McBee and his coworkers have reported that the bromination of alkanes containing fluorine occurs only at elevated temperatures.

Methyl fluoroform, when reacted at 500° at a contact time of 25 seconds, gave about 50% of CF 3 ^CH 2 Br, 7 % of CF 3 ^CHBr 2 , and traces of C F 2 ^- BrCH 2 ^{Br and CF} 3 ^CBr 3 . Ethyl fluoroform, C F 3 ^{C H} 2 ^{C H} 3 , at 450° yielded about 4 parts of C F 3 C H B r C H 3 and 7 parts of C F 3 ^{C H} 2 ^{C H} 2 B r along with C F 3 ^{C H} 2 ^{C H B r} 2 ^(324).

AROMATIC COMPOUNDS WITH AN ALIPHATIC SIDE CHAIN

Aromatic compounds containing fluorine in a side chain have been

known for many years. S warts first prepared benzotrifluoride by reacting

benzotrichloride with antimony trifluoride (473). In 1933 a patent was

ORGANIC COMPOUNDS CONTAINING FLUORINE 221 issued for the use of hydrogen fluoride in preparing C _e H6CF ₃ (266), and it is now made on a commercial scale by this process.

Henne has pointed out the similarity of this easily fluorinated molecule to that of CC12

=

CC1CC1 ₃ , which will also react with hydrogen fluoride or S b F ₃ without catalyst, and has concluded that chlorine atoms adjacent to an olefinic bond are replaced more readily than in other positions.

In an attempt to correlate the reactivity of some metal fluorides with other properties, Tewksbury and Haendler made a study of the vapor phase fluorination of benzotrichloride at 225° (514). The fluorides of lithium, potassium, calcium, magnesium, aluminum, and manganese gave no benzotrifluoride. With the other agents, the percentage yields were: N a F , 15; ZnF ₂ , 70; CdF ₂ , CoF ₂ , 18; P b F ₂ , 45; SbF ₃ , 60-65; BiF ₃ , 29; CuF ₂ , 44. The results show that the reactive fluorides are those of metals, except sodium, with oxidation-reduction potentials below manganese, but there is no parallelism between yield and potential.

There appears to be no correlation between activity of the fluorides with the crystal structures of the fluorides or chlorides nor with their solubili­

ties in organic solvents.

Compounds containing more than one methforyl group are readily prepared. In the 1930's, German chemists had prepared the three isomeric bis (methforyl) benzenes, and the preparation of tris (methforyl) benzenes has also been reported (239, 241).

I t is of interest to note that a somewhat involved procedure is used for the preparation of l,2-bis(methforyl)benzene.

C H ₃ CC1 ₃ C F ₃

Since the chlorination of o-xylene does not proceed beyond the penta- chloro stage, it is necessary to replace the bulky chlorine atoms by smaller fluorine atoms before the last hydrogen atom can be removed.

Certain ring-substituted derivatives of benzotrifluoride may be made

easily. By nitration, chlorination, or bromination, the corresponding

meta-substituted compound may be obtained from which a wide variety

of other substances may be made by the usual synthetic methods. For

instance, ra-bromobenzotrifluoride has been converted to th^ Grignard

222 PAUL TARRANT

reagent from which alcohols, olefins, etc., containing the 3-methforyl- phenyl group have been obtained (4).

In cases where the methforyl group is desired ortho or para to some other group, a different approach must be used, since ordinary substitu­

tion reactions such as nitration and halogenation take place exclusively in the meta position of benzotrifluoride. In some instances, the group desired may be introduced in the ortho or para position of toluene which may then be chlorinated and treated with antimony trifluoride or hydro­

gen fluoride to give the substituted benzotrifluoride. In such a manner, the ring-substituted nitro and chloro compounds have been made. fhe preparation of the o- and p-bromobenzotrifluoride has not been carried out by this procedure because no satisfactory method has been found to chlorinate the bromotoluenes without removing the nuclear-bound bromine; instead, Jones made a number of phenols, fluorides, chlorides, bromides, and iodides by the diazonium transformation of o- and p- aminobenzotrifluoride (261). The amino compounds were made by rather lengthy syntheses; the synthesis for the p-compound is shown.

0 2N — f ~ \ — C H 3^ 0 2N — ^ y > —

C B R 3

S b F 3 ^{jf~\ SnCl} 2 ^{/ - \}

> 02N—(/ Y-CF

• H2N—(/ > - C F

NaNOi; HBr B r — ^ ~ y ~

C F ' <

A somewhat more convenient synthesis of p-bromobenzotrifluoride has been carried out by the bromination of ra-aminobenzotrifluoride, which is commercially available, followed by the deamination by hypo- phosphorous acid of the amino group ; in this synthesis, some o-bromobenzo- trifluoride is also obtained (287). Recently Benkeser and Severson have found that o-bromobenzotrifluoride may be made in 2 8 % over-ail yield by the metallation of benzotrifluoride with n-butyllithium followed by a reaction with bromine (23).

Under most circumstances compounds containing methforyl groups on an aromatic nucleus are remarkably stable. For many years, the pro­

cedure used for making trifluoroacetic acid consisted of the oxidation of ra-aminobenzotrifluoride with dichromate, whereby the aromatic ring was destroyed. However, under the influence of concentrated acid, the

— C F 3 group can be converted to the carboxylic acid group, and such a

reaction has been used to advantage in proving the structures of many

such compounds (282). In compounds containing both the methforyl and

ORGANIC COMPOUNDS CONTAINING FLUORINE 223 the difluoromethyl groups, the difluoromethyl group can be hydrolyzed and, as a result, trifluoromethylbenzaldehyde is formed.

McBee and coworkers report that chlorination of the bis(methforyl)- benzenes in the presence of conventional catalysts and at temperatures approaching the boiling point of the fluorides does not occur (325).

Bradsher and Kittila have shown that 1,3-bis (methforyl) benzene can be made to react with chlorine to yield the 5-chloro derivative at tempera­

tures of 150 to 170° and a chlorine pressure of 20 atmospheres (48).

McBee and Pierce have reported that l-ethforyl-4-(methforyl)benzene may be obtained from the corresponding chloro compound by fluorination with a mixture of antimony trifluoride and antimony pentachloride for 7 hours at 165°. However, the octachloroethyltoluene must be highly purified if the fluorination is to be successful (333).

An attempt to introduce the pentafluoroethyl group into benzene was made earlier by Simons and Ramier, who made use of the Friedel- Crafts reaction between trifluoroacetyl chloride and benzene to yield trifluoroacetophenone (451). The ketone was then treated with PC1 5 ^to give C 6 H 5 C C I 2 C F 3 in yields of about 4 5 % . The latter compound failed to react with antimony trifluoride to give pentafluoroethylbenzene as had been expected to occur rather readily. Cohen et al. succeeded in preparing C 6 ^H 5 ^CFC1CF 3 in 3 5 % yield from C 6 H 5 C C I 2 C F 3 at elevated temperatures with antimony trifluoride and bromine (73). Simons and Herman showed that it was not possible to replace all five atoms of chlorine in CeH 5 ^CCl 2 CCl3 with the more usual fluorinating agents. They were successful in preparing a small sample of the pentafluoride with active silver fluoride made by using elemental fluorine (449).

COMPOUNDS WITH FLUORINE IN AN AROMATIC NUCLEUS

Although aromatic fluorine compounds may be prepared by the decomposition of diazonium salts in hydrofluoric acid or by the decom­

position of diazonium piperides with concentrated hydrofluoric acid, the most widely used method is that of Balz and Schiemann (11). In this procedure, the amine is diazotized by the usual agent such as nitrous acid, amyl nitrite, or nitrosylsulfuric acid, followed by the addition of fluoroboric acid or one of its salts, with the insoluble diazonium fluoro­

borate being precipitated. The solid is filtered, washed, and dried. The dried salt is then decomposed by gentle heating to yield the fluoro deriva­

tive. An alternate method consists in carrying out the diazotization in the presence of a fluoroborate so that the diazonium fluoroborate precipitates continuously as it forms; in this manner, very good yields of pure fluoro­

borates have been obtained.

224 PAUL TARRANT

Roe, in his excellent review of the Schiemann reaction, suggests that variations in the yield of fluoroborates are due to differences in solubility of the various compounds used (404). For example, the carboxyl and hydroxyl groups cause increased solubility of the fluoroborate, and when these groups are converted to esters and ethers, the yields are improved.

The highest yield of the diazonium fluoroborate from o-aminobenzoic acid has been reported to be 46%, whereas the ethyl o-aminobenzoate gives a yield of 90%. The anisidines gave o-, m-, and p-fluoroanisole in yields of 91, 82, and 85%, respectively, whereas m-aminophenol gave only a 50% yield of m-fluorophenol and o- and p-aminophenol gave none of the corresponding fluorophenols.

The decomposition of the diazonium fluoroborate generally takes place smoothly by heating the dry salt gently with a burner until a reaction is noted; frequently no additional heat is necessary to continue the decomposition. For the most part, yields in this step are good. Benzene diazonium fluoroborate has been converted to fluorobenzene quantita­

tively, while yields with alkyl groups or the halogens are 80% or greater.

Nitrodiazonium fluoroborates are troublesome to work with since they do not decompose evenly and low yields of the fluoride are obtained. For the decomposition of such compounds, it is advisable to dilute the fluoro­

borate with several times their weight of some inert material such as sand and to carry out the reaction with small quantities of compound at a time. Most of the fluoroborates decompose at temperatures of 80° or more, but the diazonium fluoroborates of a number of heterocylic com­

pounds decompose at room temperature or below.

In recent years, there has been renewed interest in the preparation of aromatic fluorine compounds by diazotization of the amine in hydrogen fluoride. Ferm and Vanderwerf have made a study of this reaction and report that in many cases yields are as good or better than those reported for the Schiemann reaction (135). The following compounds were pre­

pared successfully by Ferm and Vanderwerf in the percentage yields indicated: fluorobenzene, 87; o-fluorotoluene, 73; m-fluorotoluene, 82;

p-fluorotoluene, 78; 4-fluoro-l,3-dimethylbenzene, 57 ; 2-fluoro-l,4-di- methylbenzene, 43; ra-chlorofluorobenzene, 81; p-chlorofluorobenzene, 74; m-nitrofluorobenzene, 39; p-nitrofluorobenzene, 62; o-fluorobenzoic acid, 57; and p-fluorobenzoic acid, 98.

UNSATURATED HYDROFLUOROCARBONS

Although a large number of aliphatic olefins containing fluorine have been prepared and studied, most of such compounds also contain chlorine and have thus been treated earlier (Volume I, Chapter 15). The olefins

containing only carbon and fluorine will also be described elsewhere.

ORGANIC COMPOUNDS CONTAINING FLUORINE 225 Vinyl fluoride, as previously noted, has been prepared from acetylene.

Interest in this material and in vinylidene fluoride, C H ₂ = C F ₂ has been largely confined to their use in polymers. Park (336) has recently reported an interesting synthesis of trifluoroethylene :

Zn HBr Zn

C F ₂ C l C F C l ₂ - » C F ₂ = C F C 1 • CF ₂ BrCHFCl -> C F ₂ = C H F This material is more convenient to handle than the low-boiling (ca. —80°) vinyl fluoride, and, consequently, its reactions have been studied more extensively (363). For example, the olefin accepts bromine and chlorine readily across the double bond; methanol adds to give methyl trifluoroethyl ether, C H ₃ O C F ₂ C H ₂ F .

The majority of the other aliphatic olefins containing only carbon, hydrogen, and fluorine which have been reported have a trifluoromethyl group. The simplest of these, C F ₃ C H = C H ₂ , has been prepared by Henne as follows (212):

H F CI base

C C 1 ₂

= =

C H C H ₃ • C F ₃ C H ₂ C H ₃ —• C F ₃ C H ₂ C H ₂ C 1 • C F ₃ C H

= = : C H ₂ Henne and coworkers have shown that this olefin is rather unreactive owing to the effect of the — C F ₃ group (190). In contrast to the hydro­

carbon, C H ₃ C H = C H ₂ , the electronic displacement of the double bond is toward the — C F ₃ group so that hydro acids add, but with difficulty, to yield compounds of the type C F ₃ C H ₂ C H ₂ X . Water could not be added and polyacrylates were formed in concentrated sulfuric acid. Addition reactions of CHC1 ₃ and ^CCI4 catalyzed by peroxides and polymerization in the presence of a peroxide did not take place. More readily decomposed compounds, such as C F ₃ I and CCl ₃ Br, have been found to add to C F ₃ C H = C H ₂ under the influence of ultraviolet light (195). Iodotrifluoro- methane gave C F ₃ C H I C H ₂ C F ₃ whose structure was shown by dehydro- halogenation to the known C F ₃ C H = C H C F ₃ . Goldschmidt has reported that both C F ₃ C H = C H ₂ and C H ₂ = C ( C F ₃ ) C H ₃ can be made to undergo polymerization in the presence of a free radical initiator and a co-solvent for the monomer and the initiator (153) ; however, Friedel-Crafts reagents were unsuccessful as polymerization catalysts.

Trifluoropropyne, C F ₃ C = C H , has recently been prepared and its properties studied (194). The most successful synthesis was carried out as follows:

SbFa KOH Br

CC1 ₃ CH ₂ CH ₂ C1 > C F ₃ C H ₂ C H ₂ C 1 • C F ₃ C H = C H ₂ - +

KOH Br KOH

C F ₃ C H B r C H ₂ B r • C F ₃ C B r = C H ₂ - > C F ₃ C B r ₂ C H ₂ B r >

Zn

C F ₃ C B r = C H B r - > C F ₃ C = C H

226 PAUL TARRANT

The propyne forms a white silver acetylide which darkens on standing but explodes on heating. Chlorine reacts with CF3Cs=CH in sunlight to yield CF3CCI2CCI3.

An interesting property of C F 3C = C C F 3 is its ability to accept acetic acid (208). The addition of one molecule of acid gives an enolacetate, C F 3CH=

:

C ( C F 3) 0 2 C C H 3 , while two, molecules give the diacetate CF3CH2C (CF3 )(OCOCH3)2; some trifluoroacetone, CF3COCH3, and acetyl fluoride are also formed. The monoacetate can be converted in excellent yields to C F 3COCH2CF3 by reflux with butanol treated with a few drops of sulfuric acid.

Cyclobutane Derivatives

Generally, there is not a great tendency toward the formation of the cyclobutane ring in reactions of organic compounds. However, it has been found that C F 2= C F 2, CF2=CFC1, and CF2=CC12, in contrast to the other haloolefins, will very easily dimerize to give the cyclo compounds and will even react with a vast number of other unsaturated compounds to give a variety of derivatives containing the cyclobutane ring.

Investigations of the formation of CF2—CF2—CFC1CFC1 and I I CF2CF2CCl2CCl2 apparently were being conducted simultaneously in

1 1

Germany and the United States during the early 1940's. Henne and Ruh reported the synthesis and properties of these compounds and identified them by the following reactions (206) :

COOH C F 2CF2CC12CC12^ C F 2C F 2C C 1 = C C 1 ^ (CF2)2

I I I J I

COOH

These reactions offer a good method for preparing tetrafluorosuccinic acid and its derivatives.

Chemists of the duPont Company have been most active in studying the reactions of C F 2=CFC1, and C F 2= C F 2, in particular, with olefins containing a functional group to give aldehydes, ketones, acids, nitriles, and many other classes of organic compounds (17, 21).

In an excellent research study, Coffman et al. found that the synthesis of many such compounds containing the 4-membered ring occurs more readily than the dimerization of the fluoroolefin so that the yields are generally good (68). The reaction with ethylene is illustrated below:

C F 2 CH2 CF2—CH2

II + II - I I

C F 2 CH2 CF2—CH2

ORGANIC COMPOUND S CONTAININ G FLUORIN E 227 The eas e o f reactio n varie s wit h th e unsaturate d reactant . Compound s containing th e CH ₂ =group combin e mor e readil y tha n d o 1,2-disubsti - tuted compound s suc h a s 2-buten e o r trichloroethylene , whil e reactant s having conjugate d unsaturate d linkages , suc h a s occur s i n 1,3-butadiene , acrylonitrile, an d stryene , ar e eve n mor e reactive .

Tetrafluoroethylene react s wit h monoolefins , viny l chloride , viny l acetate, an d ally l alcoho l t o giv e compound s o f th e typ e :

CF ₂ —CHX I I

CF ₂ —CH ₂

With propylene , a 72 % yiel d o f methy l tetrafluorocyclobutan e wa s ob - tained; viny l chlorid e an d vinyliden e chlorid e gav e yield s o f 2 3 % an d 46%, respectively .

Tetrafluoroethylene an d acrylonitril e combin e t o for m i n 84 % yiel d cyanotetrafluorocyclobutane

CF ₂ —CHCN

I I

CF ₂ —CH ₂

which ca n b e hydrolyze d t o th e cyclobutan e carboxyli c acid . Methy l methacrylate likewis e give s excellen t yield s o f methy l l-methyl-2,2,3,3, - tetrafluorocyclobutanecarboxylate.

A wid e variet y o f ethylenicall y unsaturate d oxygen-containin g com - pounds includin g acrolein , methacrolein , viny l acetate , methy l viny l ketone, methy l viny l ether , 2-vinylfuran , an d butadien e monoxid e hav e been treate d wit h tetrafluoroethylen e t o giv e th e cyclobutan e derivativ e in yield s rangin g fro m 9 t o 77% .

Very interestin g product s ar e obtaine d fro m th e reactio n o f 1,3-diene s and tetrafluoroethylene . Th e simples t compoun d forme d i s th e 1-vinyl - 2,2,3,3-tetrafluorocyclobutane an d no t th e tetrafluorocyclohexen e whic h would b e forme d b y a Diels-Alde r reaction . Thi s compoun d ca n reac t with a secon d tetrafluoroethylen e molecul e t o giv e a produc t containin g two 4-membere d rings .

CF ₂ —CH ₂ CH ₂ —CF ₂ I I I I C F ₂ — C H — C H — C F ₂

Aliène react s t o giv e methylen e tetrafluorocyclobutane , C F 2 C F 2 C H 2 C — C H

I I

228 PAUL TARRANT and 1,1,2,2,5,5,6,6-octafluorospiro[3,3]heptane,

C H 2 C F 2

/ \ / \

C F 2 C C F 2

\ / \ /

C F 2 C H 2

Two isomeric 1:1 adducts are obtained from 2-halo-l,3-butadienes.

For example, the following are obtained from 2-fluoro-1,3-butadiene:

C F 2 — C H 2 C F 2 — C H 2

I I I I

C F 2—C—CH=CH2 CF2—C—CF=CH2

I I

F H A variety of products is also obtained from compounds containing both a double bond and a triple bond. Vinylacetylene cah form simple addition products in which either the ethylene or the acetylene bonds are involved, such as

C F 2 — C H 2 C F 2 — C H

I I I I I

C F 2—CH—C=CH CF2—C—CH=CH2 I II

The compound represented by structure II can then react with a second tetrafluoroethylene to give a bicyclic compound,

CF2—CH CH2—CF2

I I ! I I

CF2—C C H — C F 2 C F 2 C H 2

I I

CF2—CH—CeH 5 A fourth product,

can be accounted for by assuming that the vinylacetylene dimerized to give stryene, which then reacted with the fluoroolefin.

In general, the fluorocyclobutane ring retains its structure during

a number of reactions. For example, 2,2,3,3,-tetrafluorocyclobutane

carboxylic acid is readily obtained either by the acid hydrolysis of the

nitrile or by oxidation of the 1-vinyl derivative. Recently, however,

Barney, and Cairns reported (14) that the basic hydrolysis of the nitrile

splits the ring to give á,á-difluoroglutaric acid. They showed, furthermore,

that trifluorochloroethylene, water, and acrylonitrile also gave the same

compound. For these unusual reactions, the following mechanism was

proposed :

ORGANIC COMPOUNDS CONTAINING FLUORINE 229

C F 2 ^{= CFC1 H} 2 ^{0 H} 2 ⁰

C H ₂ = C H C N • CF ₂ —CFC1 > CF ₂ —CFC1

I I I

CH ₂ —CH—CN CH ₂ —CH—COOH H 2 ⁰

C F ₂ — C = 0 > CF ₂ —COOH I I I CH ₂ —CHCOOH C H ₂ C H ₂ C O O H Alcohols

The method of preparing an alcohol containing fluorine generally depends upon the number of atoms of fluorine desired in the molecule.

If a single fluorine atom is needed, the preparation may be carried out from a halohydrin or epoxy compound by reaction with hydrogen fluoride or potassium fluoride ; the preparation of alcohols containing the trifluoromethyl group generally begins with trifluoroacetic acid.

Knunyants and his colleagues have been able to form fluoroalkanols from the epoxy compounds and hydrogen fluoride by using diethyl ether as the diluent (272). In this manner, they obtained a 4 0 % yield of fluoro- ethanol and a 56% yield of C H ₂ F C H O H C H ₃ ; epifluorohydrin gave a 40%

yield of C H ₂ F C H O H C H ₂ F . These investigators claim that the reaction of ethylene chlorohydrin with potassium fluoride is in reality a. reaction of this type since it proceeds in two stages as shown:

C H ₂ C 1 C H ₂ 0 H + K F —* C H ₂ C H ₂ + KC1 + H F

\ / Ď

C H ₂ — C H ₂ + H F -> C H ₂ F C H ₂ O H

\ /

Ď

They base their ideas on the fact that C H ₂ C 1 C H ₂ 0 H when refluxed with potassium fluoride gave a 90% yield of ethylene oxide.

Saunders et al. used the chlorohydrin to give a 4 2 % yield of fluoro- ethanol, but Gryszkiewicz-Trochimowski preferred to react the acetates

(159, 423). It should be noted that fluoroethanol is quite toxic and, in its action, comparable to a-fluoroacetates.

Difluoroethanol was obtained first by Swarts by the reaction of 2,2-difluoro-l-bromoethane with mercuric oxide and water (480). More recent practice is to reduce ethyl difluoroacetate with lithium aluminum hydride.

Trifluoroethanol has been prepared by the reaction of 1,1,1-trifluoro- 2-chloroethane with potassium acetate and hydrolysis of the resulting ester; the use of potassium hydroxide in this reaction gives much lower yields due, undoubtedly, to the formation of C F ₂ = C H C 1 as a by-product.

Most investigators, however, prefer to reduce a derivative of trifluoro-

230 PAUL TARRANT

acetic acid. Campbell et al. found the most convenient method of prepara­

tion of trifluoroethanol to consist of the reduction of butyl trifluoroacetate with lithium aluminum hydride; using this procedure, they obtained a 76% yield of alcohol (58).

Trifluoroethanol is much more acidic than ethanol, as might be expected, and does not undergo many of the characteristic alcohol reac­

tions (58). It does not react with concentrated sulfuric acid at 200° nor does p-toluenesulfonyl chloride convert it to the ether. Campbell et al.

were not able to convert the alcohol to trifluoroethyl bromide by treat­

ment with phosphorus pentabromide.

The Grignard reaction is useful in the preparation of a number of compounds containing the trifluoromethyl group. Ethyl trifluoroacetate

C H 3 and methylmagnesium bromide give good yields of CH3—C—CF3,

H Τ

although some investigators have preferred to use higher esters. Unfor­

tunately, this method is not applicable to the preparation of long-chain tertiary alcohols because the use of larger Grignard reagents lead to the formation of secondary alcohols. Thus, n-propylmagnesium bromide gave a 74% yield of C F 3CHOHCH2CH3; n-hexylmagnesium bromide gave similar results, and in neither case could any tertiary alcohol be found.

Campbell et al. have shown that the secondary carbinol is formed by the reduction of the intermediate ketone CF3COR which is formed when one molecule of Grignard reagent reacts with ethyl trifluoroacetate :

MgBr

Ď Ď

II η—C 3 ^H 7 ^{MgBr |}

CF3C—C3H7 > CH3—C—C3H7 -f- C3He

1

H

They were able to isolate the ketone and to convert it to the alcohol by treatment with an excess of Grignard reagent (58).

R I Although dehydration of alcohols of the type CF3—C—R

1

is gener-

ι ο

Ç C H 3

I

ally difficult, Swarts treated CF3—C—CH3 with phosphorus penta-

OH

ORGANIC COMPOUNDS CONTAINING FLUORINE 231 bromide and obtained some of the olefin, while Henne obtained a good yield using phosphorus pentoxide at 130° with careful heating (209).

The secondary alcohols l,l,l-trifluoro-2-octanol was found to be more resistant since it was not dehydrated when heated with potassium acid sulfate, concentrated sulfuric acid, 8 5 % phosphoric acid, or phosphorus pentoxide at 235° (58). Vapor phase dehydration over activated alumi­

num at 350° gave only lower molecular weight decomposition products;

the methyl xanthate derivative could be distilled at atmospheric pressure with but slight decomposition. Finally, the carbinol was converted to the olefin in 6 5 % yield by pyrolysis of the acetate over glass wool at 500°; at temperatures sufficient to crack other molecules, the trifluoromethyl carbinol was recovered.

McBee and Truchan made use of the Grignard reagents from 1,1,1- trifluoro-3-chloropropane for the preparation of the primary alcohol 3,3,3-trifluoropropanol, while the secondary alcohol 1,1,1-trifluoro- propanol-2 has been made in very good yield by the catalytic reduction of trifluoroacetone (338).

A number of papers have appeared describing the use of ra-trifluoro- methylphenylmagnesium bromide in preparing alcohols containing the m-trifluoromethylphenyl group. In some cases, these compounds were prepared for conversion to trifluoromethylstyrene (4). Szmont, Anzen- berger, and Hartle added the Grignard reagent to formaldehyde, ethylene oxide, propylene oxide, and epichlorohydrin to give the expected alcohols (511). With propylene oxide, however, there was formed a mixture of the secondary and primary alcohols:

C F 3 C F 3

C H 2 C H O H C H 3 ^CH

\

C H 2 O H Swarts has reported the ionization constant of C H 3 C H O H C F 3 ^{to be} 1 0

-7

which indicates this alcohol is more acidic than phenol (509). Recent data by Henne and Pelley (198) give a value of 6 X 10

1 2

for this com­

pound with similar values for C F 3 ^{C H} 2 O H and C F 3 ^{C ( C H} 3 ) 2 0 H , thus indicating compounds containing a trifluoromethyl group adjacent to the carbinDl group are about 10

4

times more acidic than ethanol. McBee, Marzluff, and Pierce prepared a number of diols of the type H O C H 2 - ( C F 2 ⁾ n ^{C H} 2 O H by reduction of the ethyl esters of perfluoro acids with lithium aluminum hydride and determined their ionization constants

(332). They, too, found that these compounds were not as acidic as might

232 PAUL TARRANT

have been anticipated. Their values for the ionization constant for tri­

fluoroethanol was 5 X 10~

1 3

. The values for the first and second ioniza­

tion constants for two diols are:

H O C H 2 ^{C F} 2 ^{C F} 2 ^{C H} 2 O H 7 . 9 X 10"

13

2 Χ 10"

14

H O C H 2 ^{C F} 2 ^{C F} 2 ^{C F} 2 ^{C F} 2 ^{C H} 2 O H 7 . 9 Χ 10"

13

5 X 1 0 ~ 13

Ethers

The study of ethers containing fluorine has received a great deal of attention, especially in the last several years. There are probably two reasons for this interest in fluoro ethers: first, many can be conveniently prepared from simple fluorine compounds commonly available; second, the products formed in these reactions are sometimes quite reactive and may lead to other classes of compounds of interest in synthetic chemistry.

The fluoro ethers are generally made by the reaction of a saturated fluorohalo compound or by the addition of an alcohol to a fluoroolefin.

The latter method has been extensively investigated in the past five years.

Swarts in 1899 first prepared an ether containing fluorine by the reac­

tion of l,l,2-trifluoro-l,2-dibromoethane with potassium ethylate; he continued his studies of the reaction of other fluorohaloethanes and reported the formation of â,â-difluoro ethers from the reaction of C H F 2 ^— CH 2 Br and sodium ethylate in 1901, and later made C H 2 ^{B r C F} 2 ^{O C} 2 ^H 6 and C H B r 2 ^{C F} 2 ^{O C} 2 ^H 5 (475). In 1940 Gowland extended this method to include fluorochloro compounds by preparing ethers of the type CHC1 2 ^- CF2OR from CHC1 2 ^CF 2 C1 (155). McBee and Bolt later used sodium aryloxides to react with CHC1 2 ^CF 2 ^{C1, CH} 2 ^C1CF 2 C1, and CF3CHCICF3 to yield aromatic ethers in good yields (316, 317, 318). They noted that the chlorine of the —CF 2 C1 group was apparently displaced in preference to the supposedly more reactive chlorine of the —CH 2 C1 or —CHC1 2 groups.

The olefin-alcohol addition method was first employed in 1946 by Hanford and Rigby, who added a number of alcohols to C F 2 ^{= C F} 2 ^to give tetrafluoroethyl alkyl ethers; C F 2 = C F C 1 and C F 2 = C H C 1 were reacted with ethanol to give the α,α-difluoro ethers in good yield (170).

Miller et al. y in reporting the addition of methanol to several fluoro- olefins, postulated the following mechanism for the base catalyzed addi­

tion of alcohols to fluoroolefins (346) :

F F F F

\ / \ / R O - \ / ROH \ /

C = C -» ( + ) C—C ( - ) • ROC—C > ROC—CH

ORGANIC COMPOUNDS CONTAINING FLUORINE 233 Somewhat later Park and others showed that C F 2=CFC1 reacted with a series of alcohols to give the corresponding ethers, CHFC1CF20R, in good yield by simply passing the fluoroolefin through a solution of alcoholic potassium hydroxide in glass equipment (369). Since then, many alcohols have been added to C F 2= C F 2, CF2=CC12, C F 2= C H F , and C F 2=CHC1, and in all cases, the alkoxide group has added to the carbon atom having the greater number of fluorine atoms (367). I t has also been reported that phenols add readily to fluoroolefins, and a number of phenyl and cresyl ethers have been made by this method (513).

Although the saturated ethers are generally formed in greatest yield by the reaction of a fluoroolefin and alcohol, in some cases vinyl ethers, ortho esters, and even acids result. For example, when Ł-butyl alcohol adds to C F 2=CC12 at 100°, the principal product is (CH3)3C0CF=CC12 (512).

Hexafluorocyclobutene does not give the saturated cyclobutyl ether as expected (365). Instead, there was formed a diether of the type:

CF2—C—OR

I I I

CF2—C—OR

Later, Barr et al. reported that the monoalkoxycyclobutene, C F 2—CF

I I I

CF2—C—OR

could be obtained by reacting the butene with alcohols in the presence of a quaternary ammonium base (15).

Park et al. showed that CF2CF2CC1=CC1 reacted to give the mono- ether, CF2—CCI , with a number of alcohols. There was also obtained

I I I

CF2—C—OR

a triether having the empirical formula C4F2C1(0R)3. Although definite proof of structure of the triethers is lacking, it is believed that the formula

RO

\

c—C—CI

/ RO

F2C—C—OR may account satisfactorily for its properties (368).

Ordinarily, it has been assumed that compounds containing the

— C F 2— group are stable and unreactive. This has not been found to be

234 PAUL TARRANT

the case always with the fluoro ethers. For example, ethers such as CHF2CF2OR and CHFCICF2OR are readily attacked by concentrated sulfuric acid and the á-fluorine atoms replaced by oxygen to yield difluoro- and fluorochloroacetates; this reaction has become a convenient method for the synthesis of derivatives of haloacetic acids (554, 555). Ethers containing more than one hydrogen atom in the beta position are even more reactive; C H 2 C 1 C F 2 0 C 2 ^H 5 hydrolyzes even in water and C H 3 ^{C F} 2 ^- OC2HB is apparently too reactive for isolation under ordinary circum­

stances, since attempts to prepare it from CH 3 ^CF 2 C1 and sodium ethoxide gave only ethyl acetate (556).

The thermal stability of fluoro ethers depends a great deal on the alkyl group containing no halogen. Methyl, ethyl, and propyl difluoro- ethyl ethers can be readily distilled without decomposing, but branched chain alkyl ethers are not so stable. For example, isopropyl a-difluoro- â-dichloroethyl ether gives both isopropyl fluoride and dichloroacetyl fluoride upon distillation at atmospheric pressure; the ß-butyl ether from C F 2 = C F C 1 gives ß-butyl fluoride, isobutylene, and chlorofluoroacetic acid (512).

Polyfluoroalkyl ethers of the type formed by the addition of alcohols to trifluorochloroethylene are generally more stable than the chloroalkyl ethers (385). These fluoro compounds do not react with Grignard re­

agents, nor could they be converted to Grignard reagents themselves.

However, they react with aluminum chloride to give alkyl and acyl halides. Chlorination of such ethers occurs in the presence of ultraviolet light, and the chlorine enters the alkyl chain which contains no fluorine.

The chlorinated compounds are very stable both chemically and ther­

mally. They are not soluble in concentrated sulfuric acid, and thus do not hydrolyze in the normal manner to the halo esters.

Park, Sharrah, and Lâcher have shown that the fluorocyclobutene diethers react with alkaline permanganate to yield diethyl tetrafluoro- succinate in 80% yield. The monoalkoxypentafluorocyclobutenes can be oxidized by the same reagent, but the resulting compound is generally tetrafluorosuccinic acid rather than the ester.

Recently the idea has been presented that the reactions of saturated

fluorochloro compounds with alkoxides to yield fluoro ethers is not a

simple displacement reaction of the Williamson type, but that fluoro-

olefins are first formed which then add a molecule of alcohol to yield the

ether (556). For example, it has been found that CHF 2 ^CC1 3 and C H F 2 ^-

CHFC1 give C H C 1 2 ^{C F} 2 ^{0 C} 2 ^H 5 ^{and C H} 2 ^{C 1 C F} 2 ^{0 C} 2 H 5 when treated with

sodium ethoxide and alcohol. I t is difficult to account for their formation

by any mechanism except that involving olefin intermediates,

ORGANIC COMPOUNDS CONTAINING FLUORINE 235

- O R HOR

CHF ₂ CC1 ₃ > C F ₂ = C C 1 ₂ > CHC1 ₂ CF ₂ 0R

- O R HOR

CHF ₂ CHFC1 > C F ₂ = C H C 1 > CH ₂ C1CF ₂ 0R

It is known, of course, that saturated compounds of this type can give olefins readily and such products are quite reactive under dehydrohalo- genation conditions. Even with C F ₃ C H ₂ B r it is difficult to replace the bromine to yield C F ₃ C H ₂ O C ₂ H ₅ ; in spite of the inertness of the methforyl group, a fluorine is eliminated to yield C F ₂ = C H B r which reacts normally to give C H ₂ B r C F ₂ O C ₂ H ₅ . In these cases, the base attacks a hydrogen atom adjacent to the cluster of fluorine atoms to form HX, leaving the reactive olefins.

It has recently been shown that alcohols will add to hexafluoro- 2-butyne (63). For example, ethanol gave both C F ₃ C ( O C ₂ H ₅ ) = C H C F ₃ and C F ₃ C ( O C ₂ H ₅ ) ₂ C H ₂ C F ₃ while C H ₂ O H C H ₂ O H gave C F ₃ C H =

C F ₃

I

C(CF ₃ )OC ₂ H ₄ OH and C F ₃ C H ₂ C — O C H ₂ .

I I

Ď C H ₂

Fluoroacrylonitriles and acrylates have also been shown to form ethers with alcohols (60). Ethanol adds to C F ₂ = C C 1 C N and to C F ₂ = CFCN to give C ₂ H ₅ 0 C F ₂ C H C 1 C N and C ₂ H ₅ O C F ₂ C H F C N , respectively;

the acrylates react in an analogous manner.

Aldehydes and Ketones

The literature dealing with aliphatic aldehydes containing fluorine is relatively meager. The preparation of aromatic aldehydes is a rather simple task, since it is only necessary to introduce the fluorine atom into the nucleus of a ring containing a methyl side chain and subsequently to convert it to the aldehyde group, or to begin with an amino aldehyde and replace the — N H ₂ by a diazotization in hydrofluoric acid or by the Schiemann reaction. The number of times these operations have been carried out may be determined by an inspection of the table at the end of the chapter.

In the aliphatic series, however, these simple synthetic methods are

not applicable and, as a result, research on this class of compounds has

been neglected until recently. As late as 1944 it was stated that "fluori-

nated aldehydes are unknown" (180). In 1950, Henne and coworkers

prepared C F ₃ C H O by the reduction of trifluoroacetonitrile with lithium

aluminum hydride, while Skechter and Conrad obtained the aldehyde

by the reaction of C F ₃ C H ₂ C H ₃ with nitric acid and oxygen at about 450°.

236 PAUL TARRANT

Fluoral boils at about —18°, dissolves slowly in water, and forms a hydrate. Fluoral forms a polymer which, upon heating, decomposes readily into the aldehyde. It is oxidized by Tollens reagent and gives fluoroform when treated with a strong base. Phenylmagnesium bromide reacted with it to give a compound which was oxidized to trifluoro- acetophenone.

Aldehydes containing a methforyl group not adjacent to the carbonyl group may be made by conventional means when the proper starting materials are available. For example, C F ₃ C H ₂ C H O has been made by the dichromate oxidation of C F ₃ C H ₂ C H ₂ O H , while C F _? C H ₂ C H ₂ C H O was prepared by reacting C F ₃ C H ₂ C H ₂ M g C l with ethyl orthoformate (199, 330).

Ketones containing fluorine have received somewhat more attention than aldehydes, quite possibly because of the ease with which trifluoro­

methyl ketones can be made from the commercially available trifluoro- acetic acid. S warts in 1926 showed that ethyl acetate could be made to undergo the Claisen condensation with ethyl trifluoroacetate to yield C F ₃ C O C H ₂ C 0 ₂ C ₂ H ₅ , which gave C F ₃ C O C H ₃ by decomposition with sulfuric acid.

In 1947, Henne and coworkers obtained C F ₃ C O C H ₂ C O C ₂ H ₆ by the Claisen reaction in improved yields by making use of the insoluble copper chelate to isolate the product (197). The reaction was extended to include the condensation of ketones with ethyl trifluoroacetate, with CF ₃ COCH ₂ - COCH ₃ and C F ₃ C O C H ₂ C O C F ₃ being obtained from acetone and tri- fluoroacetone, respectively. Ethyl difluoroacetate condensed with ethyl acetate to give C H F ₂ C O C H ₂ C 0 ₂ C ₂ H ₅ ; the difluoroacetate would not condense with itself nor with ethyl trifluoroacetate when sodium ethoxide was employed as the condensing agent.

Although trifluoroacetone has thus been available in reasonable amounts only since 1948 or 1949, it has been used in several interesting syntheses. For example, a recent patent claims that trifluoromethyl- butadiene may be synthesized by the following reactions (218).

C F ₃

I M g S 0 4

C H = C M g B r + C F 3 C O C H 3 - » C H = C — C — C H ₃ >

I

ο

Ç

C F ₃ C F ₃

I [H] I

C H = C — C = C H ₂ — * C H ₂ = C H — C = C H ₂

Trifluoroacetone readily forms a cyanohydrin when treated with

sodium cyanide-and sulfuric acid (81). Treatment of the cyanohydrin

ORGANIC COMPOUNDS CONTAINING FLUORINE 237 with alcoholic ammonium sulfide gives a-hydroxy-a-trifluoromethylthio- propionamide which can be hydrolyzed with dilute acid to give a-hydroxy- á-trifluoromethylpropionic acid. Although the patent literature (100) claims that the cyanohydrin can be dehydrated with thionyl chloride and pyridine, Darrall et al. reported no evidence of unsaturated products with acetic anhydride, sulfuric acid, or phosphorus pentoxide (81).

Since then, a number of 0-diketones have been prepared by condensing various methyl ketones with ethyl trifluoroacetate (392). Such compounds are of great interest because of the fact that they form insoluble chelates with a number of the heavier metal ions.

Thenoyltrifluoroacetone

has been investigated as a complexing agent for the separation and puri­

fication of various metallic ions such as aluminum, beryllium, cobalt, copper, iron, zinc, yttrium, zirconium, and hafnium. I t has certain ad­

vantages, such as stability at lower pH's and the formation of chelates which may be sublimed under vacuum yet are not too volatile at atmos­

pheric pressures (39).

Ketones containing two trifluoromethyl groups have been reported (330). Ethyl carbonate gave an 18% yield of l,l,l,7,7,7-hexafluoro-4- heptanone with CF3CH2CH2MgCl; l,l,l,5,5,5-hexafluoro-2-pentanone re­

sulted when this Grignard reagent reacted with trifluoroacetonitrile.

A halogen exchange reaction is rarely used for the preparation of fluoro ketones although monofluoroacetone has been prepared by the reaction of bromoacetone with thallium fluoride (387).

The preparation of aromatic ketones containing fluorine has been confined chiefly to those prepared by the reaction of benzene and a suit­

able acid chloride in the presence of aluminum chloride. Simons and Ramier were the first to prepare trifluoroacetophenone, using this method.

This ketone undergoes the haloform reaction with strong bases, forms an insoluble sodium bisulfite addition product, and reacts with PCU to form the dichloride, but fails to form a cyanohydrin. Cohen et al. prepared trifluoro-, difluorochloro-, and difluoroacetophenone as intermediates for the preparation of substituted styrenes; trifluoroacetyl chloride gave a 6 1 % yield of ketone with diphenylcadmium (73).

Jones has made use of organometallic derivatives of benzyl chloride to react with CF3CN and CF3COCl to give trifluoromethyl ketones (262).

I t was first thought that benzyl trifluoromethyl ketones had been pro­

duced, but later work by Nes and Burger showed that the benzylmetallic

derivatives rearranged and that o-methylphenyl trifluoromethyl ketone