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0. C. Reference. 1. 2. H2SO4. (20). 16. 2. HSO3CI b.8. (39). 160-80. (39). 0.1 ... is one report that aluminum chloride brings about this condensation...
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Chemistry and Toxicity of Some Organofluorine Insecticides W. T. SUMERFORD

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Communicable Disease Center, Public Health Service, Federal Security Agency, Savannah, Ga.

The chemistry, insecticidal, activity and toxicity of the major organofluorine insecticides are reviewed. In the ten years since the discovery of DDT opened up a new field of endeavor for the chemist, biologist, and toxicologist, activity in the field of fluorine-containing insecticides has been great.

T h e discovery of the phenomenal insecticidal activity of l,l,l-trichloro-2,2-bis(pchlorophenyl)-ethane ( D D T ) , which occurred less than 10 years ago, opened up a new field of endeavor for the chemist, biologist, and toxicologist. The activity i n this field is considerable, and a portion of i t has been directed toward efforts-to locate useful insecticides among the fluorine-containing compounds. Some of the fluorine compounds known to be insecticidal were re-evaluated, other compounds were tested biologically for the first time, and new compounds were prepared to be subjected to such tests. Elemental fluorine, inorganic combinations of fluorine, and organofluorine compounds are known to be general systemic poisons (74). Fluorine itself appears to be about as toxic as hydrogen cyanide to certain species of insects, with the effective insecticidal concentration lying between 100 and 1000 p.p.m. (81). A number of inorganic fluorine compounds—e.g., volatile fluorine compounds (76), metallic fluorides, fluosilicates, and fluoaluminates—have been employed for some 50 years mainly as stomach poisons for household and agricultural insects (15). Furthermore, the assertion has been made that any inorganic compound containing fluorine will mothproof wool (16). More recently i m proved methods for introducing fluorine into organic molecules (1, 73) have provided samples of an increased number of fluorinated compounds for the determination of their toxicity toward insects. These developments would seem to justify a review of the pertinent information which has been published on the organofluorine insecticides, with special reference to the methods for their synthesis and to their biological activities. Such hybrids as the hydrofluorides (108), fluosilicates (100), and fluosulfonates (98) of aromatic amines and the fluoborates of some organic acids (99), although known to be active insecticides, are not included. For the purpose of this review, the compounds considered are distributed among the following sections: l,l,l-trichloro-2,2-bis(p-fluorophenyl)-ethane, analogs of 1,1,1trichloro-2,2-bis(p-fluorophenyl)-ethane, and miscellaneous organofluorine compounds. The chemistry, insecticidal activity, and toxicity of these groups of compounds are considered i n the order given. M u c h of the work i n synthetic insecticides, especially the biological portion, is necessarily of an exploratory character, and hence will have to be supported before appraisals become final.

Chemistry l,l,l-Trichloro-2,2-bis(^-fluorophenyl)-ethane. A t present, the most i m portant organofluorine insecticide is l,l,l-trichloro-2,2-bis(p-fluorophenyl)-ethane 160

AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.

161

SUMERFORD—CHEMISTRY AND TOXICITY OF SOME ORGANOFLUORINE INSECTICIDES

( D F D T ) , the ρ,ρ'-difluorine analog of D D T . D F D T was not specifically mentioned i n the original United States patent (86) issued to Paul Muller and assigned to J . R . Geigy, A . - G . However, i t is reported to have been used i n large quantities i n Germany (under the name Fluorogesarol) as an all-purpose insecticide as early as 1944 (64). D F D T can be prepared by methods similar to those used to produce D D T — i . e . , by condensing two molecular equivalents of fluorobenzene with chloral i n the presence of concentrated sul­ furic acid. T h e fluorobenzene required for the reaction was obtained i n Germany b y the fission of nitrogen from phenyldiazonium fluoride which resulted from diazotizing aniline in the presence of copper and hydrofluoric acid (106). The laboratory methods that have been used to prepare D F D T are given i n outline form in Table I . The selected items of information were not uniformly available.

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Table I. CClsCHO, Moles 1 16 0.1 0.42 c 1.1 1.1 0.8

C

0.23 0.10 0.53 0.1/

C

Synopsis of Laboratory Methods for Preparing (p-fluorophenyl)-ethane Condensing Agent Moles

PhF, Moles 2 2

H2SO4 HSO3CI

0.2 0.84 2.0 2.0 2.0

H S04.H 0 H SCM H SOi H2SO4 H S04 H S(V

0.72 0.20

2

2

2

2

8 20

Order of Mixing"

H S0 PhF 2

4

4' 4 ' 3.4

H S04 H S04 Acid

HSOjCl HSOÎCI

0.35 1.8

HSO3CI HSO3CI

0.117

HSO3CI

0.11

HSO3CI

0.25

H S04

1

H S04

2

2

2

2

2

2

Conditions Temp., Time, °C. Hours

30-50 45

36 2

' 25 0 10-20 30 Cool 5 30

"2 12 2 10

Cooled

"2 20 12 12

1,1,1-Trichloro-2,2-bis-

Yield,

%

67 28 50 81 76 68 73

M.P., C. 0

b.8 160-80 43-4 41-2 26 42-3

40 ' b.7-8 172-6 45-6

Reference (20) (39) (86) (65) (107) (10) (10) (10) (10) (109) (60) (S3)

Compound listed in this column added to mixture of other reactants. b Chloral ethylate used in place of free chloral in this reaction. Chloral hydrate used in place of free chloral in this reaction. d 60 ml. of 2 0 % fuming H S 0 4 added during course of reaction. 50 ml. of fuming HSC>4 added during course of reaction. / 1,2,2,2-Tetrachloroethyl ether used in place of chloral. a

c

2

E

2

T A B L E I . I t is probable that all the indicated yields can be improved. However, using these data as a criterion, it appears that the chloral can be replaced by its hydrate or alcoholate and that a moderate excess of fluorobenzene favors the reaction. There is one report that aluminum chloride brings about this condensation (34), but here, as with D D T , the choice condensing agents are concentrated sulfuric acid (with or without the addition of oleum), and chlorosulfonic acid (84)- A moderate temperature and prolonged stirring, which must also be vigorous, increase the yield. D F D T is usually obtained in the laboratory as an almost-white, gummy material with an odor resembling that of ripe apples. (A recent sample of technical grade D F D T supplied through the courtesy of W . M . Lee, Pennsylvania Salt Manufacturing Company, Philadelphia, P a . , met this description and melted at 35-37°C.) I n some instances, refrigeration is necessary to bring about solidification. This product is a mixture of several isomers of l,l,l-trichloro-2,2-bis(p-fluorophenyl)-ethane from which the p,p'isomer, boiling point, 133-34° C., melting point 42-43° C., can be separated by distillation at reduced pressures (10). The recrystallization of crude D F D T is attended by considerable loss due to its high solubility i n the common organic solvents. Dissolving the low-melting crude mixture i n ethyl alcohol and adding water to the point of incipient precipitation followed by cooling raised the melting point to 40° (109). Recrystallization from ethyl alcohol produced needle-shaped crystals, melting point 44-45° (79), and from methanol (twice) crystals melting at 45° (78). (The oil from which these crystals were obtained had a boiling point at 1 mm. of 133-134° and a refractive index of 1.5707 at 20° C.) The vapor pressure of D F D T (0.5 m m . of mercury at 178°) (79) is reported to be some fifteen times that of D D T (3). I n a recent study i n this laboratory, Goette found that a 400 mg. per square foot deposit of D F D T on protected glass panels lost 9 5 % of its weight in 9 weeks AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.

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162

ADVANCES IN CHEMISTRY SERIES

as compared to a 1 5 % loss for D D T (36). This has considerable influence on the ac­ tivity of D F D T as a residual insecticide. B o t h D D T and D F D T are extremely insoluble in water, but D F D T (79) is approximately ten times as soluble as D D T (61) i n such solvents as mineral oil, kerosene, dibutyl phthalate, Velsicol A R - 6 0 (a mixture of polymethylnaphthalenes supplied by the Velsicol Corporation, Chicago, 111.), carbon tetra­ chloride, xylene, o-dichlorobenzene, and cyclohexanone. These solvents are commonly used as vehicles for insecticidal formulations, thus giving D F D T an advantage over D D T in this respect. Like other 2,2-diaryltrichloroethanes, D F D T undergoes dehydrohalogenation i n the presence of a base to yield l,l-dichloro-2,2-bis(p-fluorophenyl)-ethylene. The rate of this reaction has been found to be directly proportional to the temperature, and the rate con­ stant for D F D T is approximately one seventh that for D D T at ordinary temperatures (18, 110). This ethylene derivative has been oxidized by the use of chromic anhydride to ρ,ρ'-difluorobenzophenone, a sample of which did not depress the melting point of an authentic sample prepared by a different route (10). D F D T has been subjected to the usual analysis for its halogen content, but no spe­ cific method has been worked out for its determination, nor has an investigation been made of its response to the known colorimetric reactions of D D T . Analogs of l,l,l-Trichloro-2,2-bis(^-fluorophenyl)-ethane. T h e broad a n d powerful insecticidal a c t i v i t y of D D T appears to a marked degree i n several com­ pounds related to i t i n structure. Because the a c t i v i t y of D F D T against certain species of insects compares very favorably w i t h that of D D T , several analogs of D F D T have been prepared for biological testing. Some of these analogs were o b ­ tained b y reactions corresponding to those used to prepare D F D T , while others were prepared directly from the D D T or D F D T molecules themselves. T h e reactions which have been used to prepare the D F D T analogs are outlined i n Table I I . A l l available information is included. T A B L E I I . Several of the reactions outlined i n Table I I were discussed under the chemical reactions of D F D T . I n general, the D F D T analogs listed here were prepared in the laboratory for the purpose of producing a sample of the material for biological test­ ing rather than to study the several reactions involved or to improve the yields. T h e latter were usually omitted i n the literature. Samples of l,l,l-trifluoro-2,2-bis(p-fluorophenyl)-ethane, and the corresponding bis(p-chlorophenyl) derivative were obtained b y applying Henne's fluorination method to D F D T and D D T , respectively. I n both instances a mixture of the mono-, d i - , and trifluoro compounds was obtained, but the desired trifluorinated material was separated by fractional recrystallization from methanol and cooling with a mixture of dry ice and acetone. The reactions used to prepare 2,2-bis(p-fluorophenyl)-l,l-dichloroethane and 1,1,1tribromo-2,2-bis(p-fluorophenyl)-ethane are reminiscent of those used for D D T .

Insecticidal Activity It has been demonstrated that the organofluorine compounds are capable of killing insects as either stomach or contact poisons. Some of the more volatile members of this group have a degree of fumigating action. However, most of the investigations of this group have been directed toward a determination of their activity as contact poisons. W i t h the possible exception of D F D T , too few of the organofluorines have been tested under controlled conditions to permit a definite evaluation of their usefulness even i n this one field. It is generally agreed that the contact-insecticidal activity of the D D T type of com­ pound depends on at least one toxic component and the C C 1 group or some other lipoidsoluble group for penetration. Beyond this point, there is a lack of agreement as to the exact mechanism b y which the contact insecticides exert their action. Although a lipoid-soluble group characterizes many contact insecticides, simple o i l solubility of a compound is not always a criterion of activity. Busvine (14) tested a series of D D T analogs and found that solubility i n oil was not essential to activity. K i r k w o o d 3

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163

SUMERFORD—CHEMISTRY AND TOXICITY OF SOME ORGANOFLUORINE INSECTICIDES

Table II. Synopsis of Laboratory Methods Used to Prepare Analogs of 1,1,1 -Trichloro-2,2-bis(p-fluorophenyl)-ethane Having Insecticidal Interest Reactant

Reactant (p-FC H ) CHCF (p-ClC6H ) CHCF3 (p-ClC H ) CFCFCl & (p-ClC H ) CHCF Cl (p-FC H ) CHCHCl

(p-ClCeH ) CHCCl PhF

(p-FC H ) C=CCl (p-FC H ) CH—CC1=CC1

(p-FC H ) CHCCl PhF

6

4

2

6

2

4

4

6

4

6

2

2

c

2

2

4

6

4

2

4

6

(p-FCeH ) CHCCl3 (p-ClC H ) CHCCl

3

4

6

2

2

6

2

(p-FC H ) CHCBr ( p - F C H ) (p-ClC H )CHCCl < (p-FC H ) CHOH« (p-FCeH ) CO 6

4

6

4

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6

2

3

6

4

2

4

2

4

H S0 .H 0 Oleum (26%) A1C1

3

4

2

2

3

3

SbF CHCl CH(OEt) 3

(0.2)

2

2

(0.1)

KOH/EtOH CHC1 CHC1= CC1 CBr CHO

3

2

2

3

3

HgO HgO

4

2

a

PhF (p-FC H ) C=CCl 6

Condensing Agent Moles

2

4

Excess Excess

HF° HF

0.94 0.11

2

4

2

2

Mole

Mole

Product

2

4

2

Order of Mixing

0.22 0.25

HF HF

4.5 18 ml.

Acid

Aici«

CrOj

2

Conditions Temp., Time, hours °C.

(65) (65)

Ï2*

89-90 77

(91) (85)

3 ' 15

42-42.5

(10) (85)

H2SO4

120' '

Reference

78-80 64-65

20-30 20-30 160 + Cool 20-30 Reflux 5

M . P., °C.

1.'25

b.0.2

149-150 34-36 106-107

(34) (95) (79) (10)

Liquid hydrogen fluoride. b Presumably prepared by addition of fluorine to dehydrochlorinated product of D D T . In Chemical Abstracts and in English summary of article (91). Body of paper refers to compound as ρ,ρ'dichlorodiphenyldifluorodichloroethane, but gives no analytical data. d Synthesis of this compound not given in abstracts, but similar hybrids have been prepared via l-trichloro-2-chlorophenylethanol (103). Reported as prepared by R. Picard, University of Illinois. 0

c

β

and Phillips (66) showed that both D D T and l,l,l-trifluoro-2,2-bis(p-chlorophenyl)ethane are very soluble i n fats, but only D D T is insecticidal. When fed under the same condition to rats, the D D T accumulated i n the perirenal fat of rats, while the noninsecticidal analog did not. The approximate tenfold increased solubility i n fixed oils of D F D T over D D T fails to increase its insecticidal activity i n anywhere near this ratio. These findings support the earlier postulation that the oil-water distribution coefficient of a com­ pound is more important i n this respect than its solubility i n oil (70). There are several theories concerning the mechanism by which the toxic component of a contact insecticide exerts its action. The toxicity has been credited to the condensed chlorobenzene system, which is also lipophilic i n character (70). If this is the explanation, D F D T and the other compounds depending on the fluoroaryl system for toxicity would be expected to be less toxic than the corresponding chloro compounds, for fluorobenzene is generally less toxic than chlorobenzene. A second theory advanced by M a r t i n and W a i n (77) is based on the observation that D D T and certain other related insecticides easily lose hydrogen chloride, which presumably affects vital centers of the insect. The results of some recent work of Cristol with numerous halogenated insecticides detract from this theory (17). D D T and D F D T , having similar insecticidal activities, differ considerably i n the rate at which they undergo dehydrohalogenation. Finally, a study of D D T on several enzyme systems disclosed that i t sig­ nificantly inhibited phosphatidase, possibly through an affinity for the cholesterol of the lipoid membrane of the cell (71). The comparative effect of D F D T on phosphatidase has not been reported. AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.

164

ADVANCES IN CHEMISTRY SERIES

Efforts have been and are being made to standardize testing procedures for evaluating insecticides (41, 88), but considerable variations still exist in the methods, and results therefrom are not always uniform.

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A description of the various methods requires too much space to be given here. I n general, the test insects are placed on a surface or held i n an atmosphere with known concentrations of the insecticide. I n other procedures, the insects are treated directly with a prepared spray or dust of a known strength of the compound under investigations. L a r v i cidal activity is determined by placing samples of the larvae i n water or aqueous preparations containing serial dilutions of the product to be tested. After the various types of exposure, the test insects are usually placed under optimum conditions for recovery and so held for stated observation periods to determine the knockdown and/or mortality percentages i n a given group. Busvine, using adult lice and bedbugs, obtained more precise results from the spray method (followed by forced contact on a filter paper surface) than from an exposure to the same insecticide i n the form of a prepared dust (H). The surfaces used for the contact tests range from those peculiar to the insects' habitat to those easily provided in the laboratory—e.g., glass and filter paper. Fresh deposits of several contact insecticides gave higher kills of fruit flies on glass than on filter paper (93). Contrarily, a D D T deposit on dry bamboo, bark, rusty metal screen, and pine plywood remained toxic to adult female mosquitoes longer than did a similar deposit on new sheet metal, glass, tile, palmetto thatch, and new metal screen (28). The variations i n testing apparatus, insect species, dosages, exposures, and criteria of activity render difficult the appraisal of individual or groups of insecticides. Tables I I I to X I have been arranged in an effort to show the comparative activity of the organofluorine insecticides, principally D F D T , against a variety of organisms by including a reference standard compound, usually D D T . It is recognized that it would be advantageous to compare the chlorinated and fluorinated pairs, and this is done in so far as the sketchy data permit. Table III.

Comparative Insecticidal Activity of DDT and DFDT against Insects of Diptera Order %

Insects

DDT

Adults Fruit fly Fruit fly Fruit fly Housefly Fruit fly Fruit fly Fruit fly Housefly b Fruit fly Fruit fly Fruit fly Fly

(C.

35 52 78 38 65 71 89 60 49 53.5 56.8 3+ c

vomiloria)

Larvae

Mortality DFDT 23 36 63 99 11 100 100 100 50.5 81.2 96.8 4 + c

0.04 7/sq. cm. 0.08 7/sq. cm. 0.16 7/sq. cm. 0.25% D D T , 1% D F D T " 2.5 mg. % 25 mg. % 100 mg. % 200 mg./sq. ft.

24 72*

(soy (92> (89>

72

(89)

e

A.

Pupae

Experimental Period, Hours

Dosage

With 0.025% of added pyrethrins to each, D D T (0.1%) gave 73% kill and D F D T (0.2%) gave 91%

kill. b When same dosages were tested against female flies having some degree of D D T resistance, mortality percentages were 44 and 86 for D D T and D F D T , respectively, with 7-day-old deposits, but with 18-day deposits, mortality percentages were approximately the same with both insecticides. Female flies; kill was 100 and 95%, respectively, for D F D T and D D T against male flies. à Deposit 7 days old when tested; with 18-day-old deposits, mortality for D F D T remained at 100% and that for D D T rose to 93%, both percentages based on female flies. Concentration of solution drained from vials in which mortalities were determined. / At 48 hours, same dosage of D D T gave 95% mortality and D F D T gave 10% mortality. c

e

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165

SUMERFORD—CHEMISTRY AND TOXICITY OF SOME ORGANOFLUORINE INSECTICIDES

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T A B L E I I I . I t is obvious from the data i n Table I I I that the housefly and the mosquito, i n both the adult and larval stage, are susceptible to insecticides of the D D T type. However, the extravagant claims that D F D T is far superior to D D T as a contact insecticide against flies are not borne out b y the results of controlled laboratory tests. T h e Peet-Grady testing technique used b y P r i l l (92) would indicate that i n the presence of added pyrethrins D D T is definitely superior to D F D T when applied as a spray. O n the other hand, D F D T gave higher percentage kills than D D T when flies were placed under a Petri dish and held i n contact with deposits of the compounds on glass surfaces. A comparison of the activity of these compounds against adult mosquitoes has not been reported. The testing techniques used with mosquito larvae, usually the addition of calculated quantities of the larvicide previously dissolved i n a water-miscible solvent, are somewhat more comparable. However, the results here are conflicting. T h e A. qvxjdrimoxulatus larvae are killed within 24 hours b y either D D T or D F D T at concentrations somewhat

Table IV.

Comparative Insecticidal Activity of DDT and DFDT against Insects Classified by Order Insect

Anoplura Body lice Coleoptera Vegetable weevils Flour beetles Soldier beetles Grain weevil

%

DDT 50

Mortality DFDT 50

70 81 100 78

100 91 100 63

29

24

Lepidoptera Cabbage looper Arctiid caterpillar Oakworm (larvae) Flour moth

80 65 75 62

Hemiptera Bedbugs

Experimental Period, Hours

Dosage 0 . 3 % for D D T ° 1.4% for D F D T

Referen

(14)

a

85 7/sq. cm. 15 7/sq. cm. 10 mg./63.3 sq. cm. 2.5 mg. % D D T 12.5 mg. % D F D T 2.5 mg. % D D T 12.5 mg. % D F D T

96 120 20 120-168

(79) (79) (78) (12)

120-168

(12)

100 30 35 66

10 mg./sq. cm. A d lib. 85 7/sq. cm. 2.5 mg. % D D T 12.5 mg. % D F D T

20 96 96 40

(78) (79) (79) (12)

50

50

60 55

100 52

0.53% D D T 5.0% D F D T « 2500 7/sq. cm. 2.5 mg. % D D T 12.5 mg. % D F D T

96 40

(79) (12)

Orthoptera German cockroach German cockroach

0 37

100 80

48 48

(79)

Homoptera Red scale crawlers

100

55

504

(79)

Hymenoptera Red ants Honey bees

100 100

100 100

100 7/sq. cm. 1000 7/sq. cm.

b c

(79) (79)

Thysanoptera Greenhouse thrips

50

50

Greenhouse thrips

100

37

0.001% D D T 0.006% D F D T 0.005%

24

(79)

Dermoptera Forficula

12

86

0.125 mg./sq. cm.

69

(78)

Acarina Citrus mites

50

50

Citrus mites Rat mites Rat mites

0 76 90

0 99 93