Wartime Development of Insecticides H. L. HALLER I - n i t e d S t a t e s D e p a r t m e n t of A g r i c u l t u r e , B u r e a u of Entornology a n d P l a n t Q u a r a n t i n e , Beltsville, M d .
I n t e r e s t i n insecticides wa- stiniuiatecl i n recent !earby a n u m b e r of ebents. i r i i o n g t h e m o r e i m p o r t a n t were t h e s h o r t a g e d u r i n g t h e war of s e i e r a l of t h e s t a n d a r d agr i c u l t u r a l insecticide* and t h e need for b e t t e r p r o d u c t s t o control iiise ts arid related a r t h r o p o d s affecting t h e h e a l t h of h o t h o u r a r n i r d force. and ci\ilian population. Lead, arsenic, oncl fluorine cornpountls, derris, p ) r e t h r u m , a n d nicotine were relied upon to c o n t r o l most of the i n j u r i o u insects, and copper and s u l f u r c o m p o u n d s were t h e principal fungicides. T h e di\ersiori of large q u a n t i t i e s of t h e inorganic insecticide c o m p o n e n t s t o war production a n d t h e reduction i n i m p o r t s of p!rethruni a n d r o t e n o n e g r e a t l j intensified t h e need for neu chemicals for fighting insect pest-. Because inorganic c o m p o u n d s a r e m o r e likely t o present spray -residue problems a n d because of t h e p o t e n t i a l i n d u s t r i a l aiailahilit! of a \ a s t n u m b e r of organic compound-, t h e searc.ti for new insecticides i i a m o n g
organic products. In t h e selection of c o m p o u n d s suitable for testing, t h e ytructures possessed by t h e highl) effectibe naturally occurriiip insecticides, nicotine, pyrethrins, and rotenone, h a i e s e r i e d as a p a t t e r n for s o m e of t h e work w i t h 5 ) n t h e t i c material-. In a d d i t i o n rnany cotnpountlu n r e l a t e d to t h e insecticides of n a t u r a l origin were tested. O n e of these, a dich!orodiphen: l t r i c h l o r o e t h a n e known a* DDT, merited considerable a t t e n t i o n d u r i n g t h e last t h r e e \ears. \Iore rerently o t h e r chlorinated hTdrocarbons were shown to be promising insecticides. T h e 1-hemistryof sonie of t h e m , t h e entomological resulta obtained w i t h DDT arid s o m e of i t s analogs a n d w i t h benzene hexachloride a g a i n s t se,eral species of insects, t h e effect of changes in t h e s t r u c t u r e of nicotine, py r e t h r i n s , aiid r o t e n o n e with respect to insecticidal properties of t h e resulting c o m pounds, a n d o t h e r progress m a d e i n recent ? e a r s i n t h e vheniical phases of economic entomolog) a r e presented.
HE war demands for arsenic anti lead threatened for a time T t i l e supply of one of our major groups of insecticides, the ar-
extensive studies to develop new mothproofing agents, Lauger, : 3 advanced a vorking hypothesis Martin, and Muller (35, ) which led to the discovery of D D T a5 an iusecticide. They concluded that an insecticide must have a t lea.;t two components, a toxic portion aiid a means for transporting i t to a vulnerable part of the insect,. Their work 011 mothproofing agents had indicated that the hix(p-chlorophenyl) grouping !vas toxic; for example, they had found that l,i.(p-chloroph~:nyl)julfone was an effectivc stomach poison. This compound \vas modified by tlie substitution of the lipoid-solubilizing 2-trickJoroethy1 group for t h e polar sulfone group, and the compound iiow known as D D T rerulted. Although this line of reawning was followed in the diprovery of DDT, the inode of insecticidal action of D D T is not yet clearly under-tood, and PIIartin and Wain (41) suggested that t lie toxic3 portion of the DDT molerule is the trichloroethyl group and that the rhlorophenyl rings provide lipoid solubility. I n selerting synthetic compounds witahle for teating as insecticides, it is reasonahle to choo-e ,structures such as those present in the highly effective naturally occuri,ing in~ectiride,nicotine, the pyrpthrins, and roteiioiie. .ill three posbess complicated struct ural forniulas, and a comparison of them reveals no comninii grouping to ~\-hirhinsecticidal action might kle attributed. Sicwt'ine has heen synthesized in the laboratory (44) hut' the prospects are not bright for its commercial manufacture. The qtructures of the pyrethrins ( . T I ) and rotenone (36, 37, 58) are io coniplicatd that there i.: little hope for their synthesis in the Iahoratory. niuch less 011 a conimerrial wale. Such attempts :LR have h e n inade.to prepare simple derivatives of the pyrethrins an(l rotenoiir Ivith equal or increased insedicidal action have ~ t r ~ c w i l lmet y with failure. Attempts to prepare insecticidal compounds related to iiicotirie have also in general been unsuccewful, with the exception of tlie iwmeric neonicotine. The fact that the pyrethrin$, rotenone, :ind nicotine posses (3miplic,atedstructures i-. no ream11 for assuming that ai1 organic cmipound mu-t he a large molecule or have a complicated structure to he a good in~ecticitle. Thi. i h amply demonstrated hy the
senicala. The demands for copper depleted our supply of Paris green and copper fungicides. Of the more important insecticidal plants-pyrethrum, totlacco, and the rotenone-containing plants, derris and lonchocarpuq---only tohacco is produced commercially in this countq-. More than of our pyrethrum comcs from Kenya Colony, Hritih Ehqt Africa. Shipping interference *and adverse gron-iiig cnnditions reduced the imports of this important inserticide, and at the same time the military demtzndr: for it increased greatly. Mwt of our derris conies from British M d a y a and the Dutcnh E h t Indies, and lonchorarpus i i imported from South A4niericaa. K i t h the fall of Singaporcx t o thr Japanese the shipmerit. of drrri. reabed and the imports of lonchocarpus ivere insufficient t(J niret wirtiine agriculturd denland>. With tlie tiiver?ion of large quantities of the inorganic inqecticide components- lead, arueiiic., arid ropper--to ivrzr production. and uith the great reduction in imports of plant insecticides, the need for neiv cheniicals for fintiting insect pest3 \\-a. urgent. The availahility for industrial USP of a vait number of organi(7 products aiid the fact that the?- are less likely to present sprayresidue prohlenis than are the inorganic compounds directed t l i ~ development of neiv insecmticidee towards the utilization of organic compounds. The que-tioii naturally arises: What type.. of a t o m or groupings are needrti to produce organic. c~onnpount1i toxic to insect pests? Tlii. Ilroad question pre-ents the prohleni in it.- most gerieral aspect. It doe- not take into roilsideration the mode of actioti of insecticide. - -that i-, n-hether the c~onipoun(l acti as a fumigant, a contact iiiswtiride, or a stomach poisow nor doer; it take into awoiint thr, vaiioiis kinds of destriirtivr i n sects. In his search for organic cwiiipounds of high in.:ecstic.idal valuc the chemist has heen compelled t o work largely by the inethid of trial and error. A number of attempts have heen made t o establish a relation heta-een chemical constitution and iriaectiridal action, hut our knmvledgp in tlii. firld iilimited. I n the rnur-e o f 46'2
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Vol. 39, No. 4
INDUSTRIAL AND ENGINEERING CHEMISTRY
part of the D D T molecule is shorn in Table 11. The p,p’-
TABLEI. TOXICITY OF DDT ISOMERS TO FOURTH-ISSTAR TDE, which is l,l-dichloro-2,2-bis(p-chlorophenyl)ethane(II), LARVAE OF Anopheles quadrimaculatus Say is equal in toxicity t o p,p’-DDT, whereas p,p’-DDM, which is % Mortality after: Dosage, l-chloro-2,2-bis(p-chlorophenyl)ethane,is considerably less toxic. Isomer P.P.M. %-ET48 hr. m.p‘ 0,P’ 0,o’
a
b C
83 55
97” 82
100 73
lOOb 1OOb
0.01
30 100 35
5.0 7.5
...
0.005 0,0025 0.05 0.02 0.01 0.025
P,P’
98 77
45 176 100
...
Data from ( 1 1 ) . Data from ( I t ) . Data from (10).
I n other experiments (1) the effectiveness of p,p’-TDE closely parallels p,p’-DDT, in both household and agricultural insect control. p,p’-DDM has not been tested against any agricultural pests. The effect of replacing chlorine with bromine is also shown in Table 11. I n general the replacement of chlorine by bromine gives a compound that is less effective as a mosquito larvicide. I n addition to determining the effect of changes in the ethane part of the DDT molecule, i t is of interest t o compare the effect of replacing the chlorine atoms in the benzene rings with other atoms or radicals. Table I11 giveq the results of tests against mosquito larvae.
usefulness of hydrogen cyanide, methyl bromide, organic thiocyanates, D D T , benzene hexachloride, and many others. DDT AND RELATED COMPOUNDS
Few developments have created greater interest than the di+ covery by Muller (49) in Switzerland of the insecticidal properties of DDT. This symbol designates the product that is obtained on condensation of chloral (its alcoholate or hydrate) and chlorobenzene with a n acid catalyst. The reaction product has been shown to consist essentially of a mixture of two isomeras, l-trichloro-2,2-bis(pchlorophenyl)ethane(called p,p’-DDT) and l-trichloro-2-o-chlorophenyl-2-p-chlorophenylethane (called o,p IDDT), in the ratio of approximately 3-4 parts of p,p’-DDT to 1 part of o,p‘-DDT, together with minor constituents, including o,o’-DDT in amounts ranging from 0.007 to 4.0% ( 9 , 26). The toxicity t o mosquito larvae of these three isomers, as well as of m,p’-DDT (26), is given in Table I. The o,p’-DDT rvas synthesized by condensing chlorobenzene with 2-trichloro-l-ochlorophenylethanol, in order to ensure the absence of p,p’-DDT. m,p‘-DDT was obtained in a similar manner. The o,o‘-DDT rvas isolated from technical DDT. T h e mode of its isolation precludes the presence of any p , ~ ‘ - D D T . At 5% concentration the o,p’-DDT was also nontoxic to adult houseflies. I n tests against body lice by the beaker method (4, o,o’-DDT gave no kill a t 0.2%, whereas p,p’-DDT gave 100% mortality a t this concentration. Although o,p’-DDT is relatively nontoxic to adult houseflies, mosquitoes, and body lice, it is a n effective mosquito larvicide (89). The toxicity t o mosquito larvae of compounds formed by rcplacing one and two chlorine atoms by hydrogen in the ethane
TABLE 111. TOXICITY OF FOURTH-IXSTAR L ~ R V AOE F Anopheles quadrimaculatus OF D D T ANALOGS IN WHICHCHLORISE ATOMS I N BENZENE RINGSHAVEBEES REPI.4CED WITH OTHER ATobrs OR RADICALS (12) Substituents on Diphenyltrichloroethane p,p’-di-C1 ( D D T ) p,p’-di-Br p,p’-di-F p,p’-dl-CHsO p,p‘-di-OH p.p’-di-H p,p‘-di-CHI p.p’-di-fert-Butyl p,p’-Cl,H
Dosage, P.P 51. 0 005 0 005 0 01 0.01
-
10 01 0 01 10
0.01
% Mortality after 48 H r 100 100 85 100 20 25 100 20 85
The results of tests n-ith several D I I T analogs against four insects of economic importance are given in Table IT’. Damage by European corn borer larvae in 1945 was estimated a t 37 million dollars (56) and that by screwworm larvae, a serious pest of livestock throughout our South and especially Southwest, a t 5 million dollars. The yearly damage by houseflies is estimated a t 66 million (28). The damage by codling moth larvae to apples and other fruits is estimated to be about 31 million dollars annually and would be considerably larger, except that approximately 40 million pounds of lead arsenate are used annually for its control. Only p,p’-DDT is highly effective against all these pests. The replacement of chlorine by bromine, hydrogen, or methyl yields products that are less useful as insecticides. The substitution of tert-butyl or hydroxyl for chlorine gives compounds of relatively little insecticidal value. Acetylation of the compound having hydroxyl groups gives a compound that is also insecticidally inTABLE 11. TOXICITY OF VARIOUSDDT ANALOGS TO FOURTH- ert, but methylation of the hydroxyl group gives a compound INSTAR LARVAEOF Anopheles quadrimaculatus that is effective against codling moth and screwworm larvae D ~ %~Mortality ~ after: ~ ~ , and adult houseflies. According to Prill et al. ( 4 6 ) ,the methoxy Compound P.P.M. 24 hr. 48 hr. analog gives good knockdown, whereas p,p’-DDT does not. REPLACEXENT OF CHLORIKE BY HYDROOEN The toxicity of DDT analogs having more than one substituent 83 97” p,p’-DDT, (p-CICgHdzCHCClr 0 005 i n the phenyl radicals is also shonn in Table IT’. The introduc0 0025 55 82 p,p‘-TDE, (p-ClCaHi)zCHCHClr 0 005 88 1OOh tion of both chlorine and hydroxyl gives a product that is in0.0025 58 95 p,p‘-DDM, (p-ClCsHI)zCHCHzCI 1 0 100 100b sccticidal but on methylation of the hydroxyl groups toxicity is 01 55 100 destroyed. This is the reverse of the effect when hydroxyl only 0.05 5 40 is present. REPLACEMEST OF CHLORISE BY B R O M I N E ~ p,p‘-DDT (p-ClCsH,),CHCBra (p-BrCsHa)nCHCBrg (p-CICsH,)rCHCHBrz (p-BrCsHi)zCHCHBrp
0.00.6 0.1
0.05 1.0 0.1
ul .. 01
‘0
Data from (11). b Data from (IS) C Unpublished data from Orlando, Fla.. laboratory.
a
... ... ... ...
60 85
25 50
DDT COMPARED WITH PARIS GREEN, PHENOTHIAZINE, AND PYRETHRUM
For more than twenty years Paris green has been used the ivorld over t o combat malaria-carrying mosquito larvae. illthough it is effective for this purpose and is low in cost, Paris green breaks down to form water-soluble arsenic compounds that do not control the larvae and are toxic to fish and plant life. Table V shows comparative toxicities of p,p’-DDT and Paris
April 1947
OF SOMED D T ANALOGS TO VARIOUS TABLEIV. TOXICITY INSECTS
Codling moth larvae (48).
Substituents on Diphenyltrichloroethane ANALOGS
p,p’-di-C1 ( D D T ) p,p’-di-Br p-CI, p’-H p,p’-di-H p,p’-di-CHa p,p’-di-farl-Butyl p,p‘-di-OH p,p’-di-CHsCOO p,p‘-di-CHiO D D T olefin di-Rr-DDT olefin
a
b C
469
INDUSTRIAL AND ENGINEERING CHEMISTRY
4 lb./100 gal.
HAVISQO N L Y 100 68 96 53 91 13 6 1 97 15 10
% hlortality Corn borer larvae
(43,
8 lb./100 gal.
Housefliesa, 1% s o h .
Screwworm Larvaeb, hlin Lethal Concn.,
INSECTS NOT CONTROLLED WITH DDT
%
O S E SUBSTITUENT
100 100 100 19 17 3 2 4 19 100 32
100
io0 .. 79
2 ... ...
85e 2 1
0.01250 025 0.67 0.67 0.67 0.67 0.67 0.67 0.67 0.05-0.1 0.67 0.67
VI the concentration given for pyrethrins includes any cinerin present in the preparation. About three times as much pyrethrin and more than fifty times as much o,p’-DDT as p,p’-DDT are required to give 50% mortality of adult houseflies (16).
’
ANALOGSHAVINQM O R ETHASO N E SUBBTITUENT 2 .. 13 92 1 3 .. 11 .. 100 100 25 1 .. 1 ... .. 2 100 ... 2 .. 0 ... 12 .. 1 ... L-npublished d a t a f r o m W . A . Gersdorff. t-npublished d a t a from C . S. Rude. 0.4% concentration ( 4 6 ) .
green. Since Paris green is insoluble in organic solvents, the only direct comparison that can be made between it and p,p’D D T is in dust applications. It will be seen that a 0.1% D D T dust was completely effective a t a. dosage of 0.005 pound of D D T per acre. I n practical use D D T can be used at a strength as lorn as 1% without seriously impairing its efficiency, whereas such a large proportion of carrier is known to reduce the efficiency of Paris green (IS). In 1934 Campbell and associates (6) demonstrated the effectiveness of phenothiazine in destroying culicine mosquito larvae. Their findings were confirmed by Mail (40) and Zuckel ( 5 7 ) . Recently the compound has been recommended ( 7 ) for use in fire buckets and watering troughs t o prevent mosquito breeding, as it has been shown t o be less toxic to animals than Paris green. Table T.’ shows that, when applikd as suspensions made from acetone solutions, p,p’-DDT is more than 200 times as toxic as phenothiazine. One of the oldest insecticides and one of the most widely used against mosquitoes and houseflies is pyrethrum, the insecticidal principles of which are the pyrethrins and the cinerins (35). An outstanding feature of both the pyrethrins and the cinerins is the rapid paralytic action, commonly referred to as knockdown, which they exert upon insects. The cinerins, like the pyrethrins, are esters, and there are two. One is closely related t o pyrethrin I, the other t o pyrethrin 11. Methods of analyses do not differentiate between the pyrethrins and cinerins, and in Table
Although p,p’-DDT is effective against a nider range of injurious insects than any other organic insecticide thus far tebted, it is not a panacea for all ills due to insects. D D T has little or no effect on the boll weevil, an insect that is estimated to cause or on about 100 million dollars worth of damage every year (B), the cotton leafworm, the cotton aphid, the Mexican bean beetle, red spiders, cattle grubs, adults of the Florida and California red scales, the sugar-cane borer, orchard mites, the parlatoria date scale, and the plum curculio. It is effective against some aphids but as a rule is less effective than nicotine. It has also registered failures for one reason or another against the tobacco hornworm, the cabbage seedpod weevil, the tomato russet mite, etc. BENZENE H E X A C H L O R I D E
In March 1945 the outstanding insecticidal properties of the gamma isomer of benzene hexachloride were made public by Slade (50) in England when delivering the Hurter Lecture. Benzene hexachloride, or more correctly, 1,2,3,4,5,6-hexachlorocyclohexane, owes its discovery as an insecticide to the war. I n 1941 the need of a substitute for derris (rotenone) was acute. Chemists of the Imperial Chemical Industries reviewed their te-ts of thousands of synthetic organic compounds and selected about forty for further evaluation. -4mong them were the hexachlorides of mono- and o-dichlorobenzenes, both chosen primarily because of their bad odor, the thought being that they might act as repellents. T h e n called upon for samples of these compounds, one of the laboratories of the Imperial Chemical Industries suggested that the parent compound, benzene hexachloride, be included. The technical samples furnished proved more effective as a n insecticide than the original laboratory preparations. After considerable investigation the toxicity n as traced to the gamma isomer.
TABLE VI. COhlPARlTIVE TOXICITY TO ADULTHOUSEFLIES OF p,p’-DDT, o,p‘-DDT, AND PYRETHRINS (18) Compound p,p’-DDT o,p’-DDT Pyrethrins
Conon., hlg./Ml. 1.00 0.50 60 40 1.18 2.30
hlean Mortality in 1 D a y , % ’ 93 57 91 78 40 74
hlean Concn. Causing 50% Mortality, Mg /Mi. 0.5
... ... 1.4 ...
27
The gamma isomer of hexachlorocyclohexane, known as Gammexane in England, is one of four isomers obtained when chlorine is added t o benzene in the presence of light. (The isolation of a fifth isomer n a s announced by IC. C. Kauer, R. B. TABLE COMP.4RATIVE TOXICITIES O F D D T , PHEKOTHIAZIXE, AND PARISGREEK TO Anopheles quadrimaculatus (13) DuTall, and F. W. Alquist a t the Chicago A.C.S. meeting in Dosage, % Mortality September 1946.) According to Slade (50), J. C. Smart of ImInsecticide P.P.M. in 48 Hr. perial Chemical Industries found that the four isomers are formed Acetone suspensions from benzene and chlorine in the following proportions: alpha p,p’-DDT 0.005 94 0,0026 55 up t o 70%, beta 570, gamma 10 t o 12%, am1 delta 13 to 15%. 79 Phenothiazine 1.0 0.1 10 T h e isomers can be separated by fractional crystallization from organic solvents. Pounds per acre Talc dusts The models of the cyclohexane molecule indicate that two p,p’-DDT, 0.1% 0,005 100 forms are possible, the “boat” or “C” form and the “chair” or 0.0015 87 Paris green, 5 % 0.1 85 “Z” form. However, no isomeric forms of cyclohexane have 0.05 76 been isolated up to the present time, probably because the two 0.025 49 forms are in equilibrium. If i t is assumed that all the carbon
v.
INDUSTRIAL AND E N G I N E E R I N G CHEMISTRY
470
Goi H
CI
CI H
ube in the control of hou>ehold in;.ects. I t has alio been found (by J. E. Fahey) that, when terhnical benzene hexachloride is applied to apples several ueeks before harvesting, they acquire a musty flavor \\hicli ieduce. their market value.
.
beta
GI
H
>-,--c a fumigant for delousing rlothing and equipment of t r o o p (39).] The requirements of the powder ivere that, in addition to killing the lice present in the clothing at the .time of treatment, it should render the treated clothing lousicidal for several days and th:it it be nontoxic to man when in contact with the body for long periods (Figure 3). -4t that time information on DDT had not reached this country. After numerous trials of ninny coiiipoundr, a powder designated as M I L powder was recommended und adopted by the Army (4). This ponder contained the following ingredients : Pyrethrins (20% pyrethrum extract) S-Isobutylundecylenamide (synergist) 2,4-Dinitroanisole (ovicide) Isopropyl and diisopropyl cresols (antioxidants) Pyrophyllite (diluent) t o make
0.270 2 2
0.25
io0
The inclusion of a synergist in the formula was deemed essential because the supply of pyrethrum was limited. Although a number of compounds xere found that increased the effectiveness of t,he pyrethrins against lice, .Y-i~obutylundecylenamide ( 2 ) jva- outstanding in its performance, Alone as a 27, powder this compound was nontoxic to lice, hit w$en combined with 0.01% of pyrethrins this amount gave complete kill of lice in 24 hours. T o achieve this mortality with pyrethrins alone a powder containing 17,of pyrethrins is needed. The iV-isobutylundecylenamide therefore increased the toxicity of the pyrethrins approximately 100 times. Because powders containing pyrethrins deteriorate in storage, an antioxidant, was included. The mixture of isopropyl and di-
Unpublished d a t a from Orlando, Fla., laboratory
The toxicity of p,p’-DDT, the gamma isomer of benzene hexachloride, and of the pyrethrins to houseflies (19) is compared in Figure 2. Because the three toxicants differ in their rates of increase of toxic action with increase in concentration, the relative concentrations required to cause equal mortality are different a t different mortality levels. At the 50% mortality level ybenzene hexachloride is about nine times as toxic as p,p’-DDT and about eighteen times as toxic as the pyrethrins. Like DDT, benaene hexachloride is effective against numerous agricultural insect pests. It has been found promising against aphids, grasshoppers, wireworms, and several cotton insects, including the boll weevil but not the bollworm. DDT, on the other hand, is very toxic to the bollworm but of little value against the boll weevil. I n the manufacture of benzene hexachloride a small amount of a by-product is formed which gives the technical product a pungent, disagreeable odor. This characteristic odor may limit its
93
;84 1
3
69
[r
2
50
5
31 16
w
a
7 2 0.02 GO3 a04 a06
0.1
0.2 0.3 0.4 0.6
CONCENTRATION-MILLIGRAMS
1.0
2.0 30 4.0 6.0
PER M I L L I L I T E R
Figure 2. Comparative Toxicity of p,p’-DDT, Gamma Isomer of Hexachlorocyclohexane, and the Pyrethrins to Houseflies 0 y-Hexachlorocyclohexane 0 P,P’-DDT X
Pyrethrins
April 1947
I N D U S T R I A L A N D E N G I N E E R I N G C H E M 1.S T R Y
471
isopropyl cresols that was selected w a s av:iilable as a by-product in the manufacture of thymol from crebol and propylene. The combination of pyrethrum estract, synergist, and antioxidant n-as not ovicidal. =is the duration of effectiveness of the powder was shorter than the incubation period of louse eggs (usually 9-16 days), :in ovicide n-ns deemed desirable. Teqtiiig of numerous compounds ( 1 6 ) shoxed 2,4-dinitroanisole to \,e onc of the most effective louse ovicides. Because i t is also a i l effective lousicide and is commercially available, it wns incliidrrl in the formula. ,AEROSOL METHOD OF DISPERSIKG 1NSECTICII)F:S
Another development that played a prominent role during tlic war in controlling flying insects, such as disease-carrying mo-quitoes and flies, is the aerosol method of applying insecticide(@). The term "aerosol" was proposed about 25 years ago by Donnaii "to denote a system of particles of ultramicroscopic siw dispersed in a gas" (66). By this method the insecticide stah-suspendcd and active longer than Then applied as a spray. There a r e numerous ways of producing aerosols, but n C O I I V C I I ient one employs a liquefied gas (62). The insecticidal coniponents are dissolved in the liquefied gas, and, when the pres>iire on the ,solution i, released through a small orifice, the liquid P+capiiig into tlie atmosphere carries the insecticide Kith it and dihperses it in very finely divided form (Figure 4). A numher of insecticides arid liquefied gases haye been experimented witli aaerosols, but the conibination most esten.ively used duriiig the war comisted of 4°C of riyretlirum estract ( 2 0 5 pyrettirirr.) a r r t l 6'34 of sesame oil dissolved in ~1ictilorodifluoroInrtlr:iti~ (I-woii12). Approsimately 35 million 1-pnund :ierosol "tiomh~" containing this solution \yere nianufacturcti for our arnled force> during the war (2.3). Tlie zubsequeiit discoyrry o f I>DT 1 ~ d to the incorporation of thi. iii ticitle in the nerwol forniiil:itioii-. The following formii1:r \ \ : I ? rwonimfwded t o tlie :irmrd ftircc.: N1~YEK(;IS'I'S
If tile :ior~i.ol coiittliiiiiip pyretlii.iim : ~ i i t lswame oil i,. to have niasimum ofFectivcnw~,tlir srs:?nie oil must contain swamin. The u>efiiliie$s o f thi. coni1)outid for iiicre:i:;ing t h r kill due to pyrethriini i- t l i c rr>.ult of : i n oi)wi,v:\tioiini:itle liy 1:igIes~in(16) T h e ii,w ( i t iiii :iero.ol yrtrtle uf DDT, \vliicli is a purified grade of that tlir addition of 1 to 5'; c ~ f>es:inic oil t o a kerosene solution of technicd DDT :+lid coii.sists esseiitially of p,p'-DDT, is necespyretlirrim :i1ipreciatily inrix,: ied it.. rffectivrmess :igaiiist housesary because the technical DDT has lieeii found to corimde thc. inie nil tilolie did tiot kill the flies, and it \vna the only metal aerosol coiitainer. The cyclohesxnone wa3 added as an one of some 1 2 vegetnlilr nnd animal oily tested XvIiicIi had this auxiliary solvent to hold the DDT in solution, Freon-12 being effect. Products t1i:it increase the kill of insecticides t a poor solvent foi org:iiiic compounds. The lubricating oil nitis little or no toxicity ~ ~ l i uretl r n aloiie iire Iiiiovin ns synerg' &Atthe riiggwtiun of k;agleson :I chemical stud was undertaken hy Hnllar aiid rn-\vorkera ( 2 ; ) . TABLE VIII. EFFECTIVEKESS AGAINST HOUSEFLIES OF S'ARIOU.~ FRACTIONS OF SESAME OIL, WITH A N D WITHOUT PYRETHRUM, separated iiito four fractions by meiini of high v:icuum distilIation. Each fraction n-as ,separately Lidded tcl pyrethrum estract ISREFINED KEROSEXE (27) in refined k ~ r o s e n eand tested againht houseflies by the turiitable (2 tests with about 150 flies each; concn. of pyrethrins, 1 mg., a n d of sesame oil and its fractions, 10 mg /cc.) method (6). The results are slio\vn in Table VIII. From the Knockdown llortality combined first and second fractioris a crystalline solid was isoMaterial in 10 AIin,, Yc in 48 Hr.. 5 lated and shoxn to be sesamin. U'lien it WV,?R added to pyrethSesame oil 0 2 Pyrethrins rins in a refined kerowie-acetone mixture, the effectiveness 100 99 f; Pyrethrins + sesame oil against flieh was greatly iricre:ised (Tahle I S ) . (loyoof acetone Pyrethrins + fraction I 100 100 Pyrethrins + fraction I1 100 91 in the kerosene is Iiecessary t o dissolve the sesamin.) It was not Pyrethrins + fraction 111 100 21 possible to obtain from thr noncrystalline sctive fraction any Pyrethrins + fraction I V 100 29 crystalline conipourid other than sesamin. Pesamiri has the follo\ying structurxl formnla: TABLEIX. EFFECTIVENESS AGAINST HOUSEFLIES OF FRACTIONS OF SESAME OIL IN REFIXEDKEROSENE PLUS10% OF ACETONE(27) (2 tests with 150 flies each: concn. of pyrethrins, 1 mg., a n d of sesame oil
fractions, 2.5 mg./cc.) Knockdown Mortality' Material in 10 Min., % in 24 Hr., % Pyrethrins 100 20 Sessmin (crystalline fraction) 0 5 Pyrethrins sesamin (crystalline fraction) 100 85 Pyrethrins -k noncrystalline residue 100 89
+
CH2-0
CH, I HC----CH I H ---'"---b€12 H,C C/+->-O--'0/
INDUSTRIAL AND ENGINEERING CHEMISTRY
472
It is a bicyclodihydrofuran substituted symmetrically with two methylenedioxyphenyl groups (3, 8). I t has four asymmctrir carbon atoms, and natural sesamin is dextrorotatory. A number of plant materials have been shown t o contain compounds related t o sesamin. Among these compounds are asarinin, found in various oriental plants and in the bark of American prickly ash; pinoredinol, a constituent of the exudate of spruce and related species; and eudesamin, a constituent of kino gum from eucalyptus. Their relation to sesamin is shown i n the formula :
R’
H 1
\-/
HC-AH
where
R’
R,R’= 02CH2 (methylenedioxy) for sesamin and R
=
OH and R‘
=
asarinin
OCH, for pinoresinol
!+-erenot repelled by dimethyl phthalate.
Rutgers 612 is an effective repellent against Aedes aegypli and A . taeniorhynchus (\Vied.) as well as certain anophelines. Tndalone, while less effective as a mosquito repellent, is effective against the biting stable, or dog, fly IStomozys calcitrans (L.) 1. When first recommended to the armed forces, the three products described were supplied separately. Later a mixture containing 60% of dimethyl phthalate, 207, of Rutgers 612, and 207, of Indalone (53) was adopted (6-2-2 mixture). Isopropyl cinnamate excels against Anopheles quadriinaculatus. It was recommended as an alternate repellent in case supplies of the other materials were inadequate. I t s pronounced odor, however, limits its use by the military. The time that these four repellents were effective against two species of mosquitoes is given in Table X. I n all cases the repellent time against Aedes aegypti was much longer than that against Anopheles giiadrimnculatus.
‘r.4BLE
x. EFFECTIVEXESS AGAISST
REPELLEXTS USEDBY
THE
R,R’= OCH3 for eudesamin
*
Asarinin is levorotatory and is the optical antipode of isosesamin, which is obtained on treatment of sesamin with alcoholic hydrochloric acid. As some of these compounds were available, they mere tested for their synergistic effect on the pyrethrins. The diacetyl derivative of pinoresinol was also included. Isosesamin and asarinin were as effective as sesamin, but pinoresinol dimethylether, the optical antipode of eudesamin, was w t h o u t appreciable synergistic action, as were pinoresinol itself and its diacetyl derivative. It was concluded from these experiments that the nature of the substituents on the benzene ring is the determining factor in the synergistic action of this class of compounds. These findings led to the preparation of numerous compounds having the 3,4methylenedioxyphenyl grouping in their structures and resulted in the discovery of a number of compounds having both synergistic and insecticidal properties (21, 45). REPELLEh’TS
Vol. 39, No. 4
Repellent Dimethyl phthalate 2-Ethyl-1,3-hexancdiol (Rutgers 612) n-Butyl mesityl oxide oxalate i h d a l o n e ) 6-2-2 mixtureIsopropyl oinnamate
hlOsQVITOFX
OF
ARMEDFORCES (54) A v . Repellent T i m e , W n . Aedes Anopheles aegypti quadrimaculatus
258
346
147 320 220
108 55 41 250 120
Ot,her repellents (5’4) that have received considerable study cisare 2-phenylcyclohexanol; 1,2,3,4-tetrah~-dro-2-naphthol; hicyclo- [2,2,1]-S-heptene-2,3-dicarboxylic acid dimethyl ester (or dimethyl carbate) ; and S-see-butylphthalimide (20). Against pest mosquitoes 2-phenylcyclohexanol is slightly better than Rutgers 612 and against flies it is better than Indalone. It has passed pharmacological tests with one exception-namely, it has proved irritating to the skin of certain individuals. B-Tetralol has shown considerable promise in marly tests against various species of mosquitoes. Cnfortunately in recent pharmacological tests by the Food and Drug Xdministration (unpublished report from J. H. Draize) it was discovered that daily
I n addition t o research on controlling adult
the Southwest Pacific showed that certain Anopheles species of mosquitoes encountered there
Figure 4. Plane Being Fumigated with Aerosol Bomb to Destroy Insect Stowaways from Foreign Countries
April 1947
INDUSTRIAL AND ENGINEERING CHEMISTRY
REPELLENT VALUE OF HOMOLOGS OF TABLE XI. COMPARATIVE DIMETHYL PHTHALATE (64) Av. Repellent Time, Min.
Phthalic Acid Ester Dimethyl Diethyl Di-n-propyl Diisopropyl Di-n-butyl Methyl-n-butyl Methyl ethyl
Aedes aegypti 258 118 11 3 12 11 342
Anopheles quadrimaculatus
108 21 9 3
16 7
18
administration of this compound to rabbits produced cataracts in the eyes of some of them. This compound is therefore definitely eliminated for use on the skin. iY-sec-Butylphthalimide and dimethyl carbate are also effective repellents. They are odorless and passed all pharmacological tests. A repellent does not have to be a liquid to be applied t o the skin. The extensive testing of liquids was due primarily to military preference for this type of repellent. A number of good solid repellents have also been found, but in general these are far more effective when impregnated in clothing than when applied t o the skin. Pharmacological studies of solid repellents had not been completed when the war ended. The object of testing a large number of liquids was not only to find compounds with outstanding repellent value but also t o correlate chemical constitution with repellency. If such a relation exists, it is not a simple one. Some of the difficulties that have been encountered are shown by a comparison of homologs of dimethyl phthalate in Table XI. COXCLUSION
b
Although much progress has been made in the development of new materials for combating insect pests, many problems must be solved before their utility as practical control measures is determined. It is necessary to know against what kinds of insects the product is effective, the stage a t mhich the insect is most susceptible-egg, larva, or adult-and the compatibility of the material with solvents, carriers, fungicides, or other insecticides. It must also be determined whether the material can be applied best as a dust, a spray, or an aerosol and whether it causes plant injury when applied either to the foliage or to the soil. I t s effect on beneficial insects, such as bees and various parasites and predators, and its toxicity to warm-blooded animals, especially man, must also be ascertained. These and many other factors need to be established before a new product finds full use in the field of economic entomology. LITERATURE CITED
Alsterlund, J., Pests, 14 ( 5 ) , 10 (1946). Bousquet, E. T.,U. S. Patent 2,166,120 (1939). Bruchhausen, F. v., and Gerhard, H., B e r . , 72, 830 (1939). Bushland, R. C., McAlister, L. C., Eddy, G. W., Jones, H. A., and Knipling, E. F., J . Parasitol., 30, 377 (1944). Campbell, F. L., and Sullivan, TT’. K., Soap Sanit. Chemicals, 14 (6), 119 (1938). Campbell, F. L., Sullivan, IF’.N., Smith, L. E., and Haller, H. L., J . Econ. Entomol., 27, 1176 (1934). Chandler, A . C., Calif. Mosquito Control Assoc. Proc. and Papers of lSth Annual Conf., p. 86 (1944) [Processed]. Cohen, W. D., Rsc. trav. chim., 57, 653 (1938). Cristol, S. J., and Haller, H. L., J . Am. Chem. SOC.,69,510 (1947). Cristol, S.J., Haller, H. L., and Lindquist, A . W., Science, 104, 343 (1946). Deonier, C. C., and Jones, H. A., Ibid., 103, 13 (1946). Deonier, C. C . , Jones, H. A . , Haller, H. L., Hinchey, E., and Incho, H. H., Soap Sanit. Chemicals, 22 ( l l ) , 118 (1946). Deonier, C. C., Maple, J. D., Jones, H. A., Hinchey, E., and Eide, P. AT., J . Econ. Entomol., 38, 241 (1945). Dickinson, R. G., and Bilicke, .C., J . A m . Chem. SOC.,50, 764 (1928). Eagleson, C., Soap Sanit. Chemicals, I8 (12), 125 (1942). Eddy, G. W., W a r Med., 6, 319 (1944). Ford, J. H., U. S. Patent 2,138,540 (1940). Gersdorff, W. A., Soap Sanit. ChemicaZs, 22 (3), 126 (1946)
413
(19) Gersdorff. IT’, 4..and McGovran, E. R., Ibid., 21 ( l l ) , 117 (1945). Gertler, S.I., U. S. Patent 2,389,427 (1946). Gertler, S. I., Fales, J. H., and Haller, H. L., Soap Sanit. Chemicals, 19 (4), 105 (1943). Goodhue, L. D., ISD. ESG.CHEM.,34, 1466 (1942). Goodhue, L. D., Sci. Monthly, 61, 413 (1945). Granett, P., and Haynes, H. L., J . Econ. Entomol., 38, 671 (1945). Hall, S. A , , Travis, B. V., and Jones, 13. A , , U. S. Patent 2,390,249 (1945). Haller, H. L., Bartlett, P. D., Drake, N. L., Newman, M. S., Cristol, S. J., et al., J . A m . Chem. SOC.,67, 1591 (1945). Haller, H. L., hlcGovran, E. R., Goodhue. L. D., and Sullivan, TT’. N., J . Ow. Chem., 7, 183 (1942). Hyslop, J . A , , U. S. Bur. Entomol. and Plant Quarantine, E 4 4 4
IProcessedl. Jones, H. A.,’Incho, H. H., and Deonier, C. C., J . Econ. Entomol., 39 A72 - - flR4AI. I
\ - - - - ,
Kilgore. L. B., U. S. Patent 2,070,603 (1937). Kirkwood, S.,and Phillips, P. H., J . Biol. Chem., 163, 251 (1946). KnirJlina. E. F., and Dove, W.E., J . Econ. Entomol., 37, 477 (i944J. Liuger, P., Helv. Chim. Acta, 27, 71 (1944). Lauger, P., Martin, H., and Muller, P., Ibid., 27, 892 (1944). LaForge, F. B., and Barthel, W. F., J . Org. Chem., 12, 199 (1947). LaForge, F. B., and Haller, H. L., J . A m . Chem. SOC.,54, 810 (1932). Ibid., 58, 1777 (1936). LaForge, F. B., Haller, H. L., and Smith, L. E., Chem. Revs., 12, 181 (1933). Latta, R., and Yeomans, A. H., J . E c ( J ~Entomol., . 36, 402 (1943). Mail, G. A , , Ibid., 29, 1144 (1936). Martin, H., and Wain, R. L., Nature, 154, 512 (1944). Moore, W., and Buc, H . E., U. S. Patent 1,727,305 (1929). Muller, P., Swiss Patent 226,180 (1940); U.5 . Patent 2,329,074 (Sept. 7, 1943); Reissue 22,700 (Dec. 4, 1945). Pictet, ii., and Rotschy, A., Ber., 37, 1225 (1904). Prill, E. A., Hartaell, A,, and Arthur, J. M., Contrib. Boycs Thompson Inst., 14 (31, 127 (1946). Prill, E. A., Hartaell, -4., and Arthur, J. &I., Science, 101, 464 (1945).
Questel, D. D., and Gertler, S.I., U. S. Bur. Entomol. and Plant Quarantine, E-612 [Processed]. Siegler, E. H., and Gertler, S. I., J . Econ. Enfomol., 37, 845 (1944).
Simmons, J. S.,Kentucky Med. Jour. (1945). Slade, R. E., Chem. Trade J., 116 (3017), 279 (1945); Chemiat r y & Industry, 64, 314 (1945). Staudinger, H., and Ruzicka, L.. Helv. Chim. Acta, 7, 177 (1924).
Sulliran, TT’. N., Goodhue, L. D., and Fales, J. H., J . Econ. Entomol., 35, 48 (1942). Travis, B. V., and Jones, H. A., U. S.Patent 2,356,801 (1944). U. S. Bur. of Entomol. and Plant Quarantine, Rept. 158 to Com. on bled. Research of O.S.R.D., Natl. Research Council Insect Control Corn. (A4pril1942 to Oct,. 1946). Vance, A. M., U. S. Bur. Entomol. and Plant Quarantine, Insect Pest Survey, Special S u p p l . No. 4 (May 1, 1946) [Processed]. Whitlaw-Gray. R., Speakman, J. B., and Campbell, J. H. P., PTOC.R o y . SOC.(London), A102, 600 (1922). Zuckel, J. TV,, J . Econ. Entmol., 37, 796 (1944). PRESENTED before the Division of Organic Chemistry at the 110th Meeting Of the AMERICAN CHEMICAL S O C I E T Y , Chicago, 111
Acetic Acid-Ethyl Ether-Water S y s t e m (Correction) Attention has been called to the following errors in our article ASD which appeared in the August 1946, issue of INDUSTRIAL ENGISEERIXG CHEMISTRY. Page 836, Figure 6: The ordinate and abscissa should be -cl),’cl” labeled “cl/(l -cl)” and “cz ’(1 -e*)’’ instead of ‘,(l and “(1-cz)/cl”, respectively. Page 836, column 2, line 6 should read “c~,’(l-el) against log ct/(l -cz)” instead of “(1 -c,)/c1 against log (1-cz)/cz)’. It m-ill be noted that a logarithmic plot of (l-cl)/c, against (1 - c2)/c2 will also yield a straight line for each of the three sets of C. J. MAJORASD 0. J. SWENSON tie line data for this system.
