Note: Descriptions are shown in the official language in which they were submitted.
~-- lO~iQ459
RING-SUBSTITUTED N-(2,2-DIFLUOROALKANOYL)-
o-PHENYLEN~DIAMINE COMPOUNDS
~ The present invention relates to novel ring-
substituted N-(2,2-difluoroalkanoyl)-o-phenylenediamine
compounds. These compounds are useful as herbicides,
insecticides, parasiticides, anthelmintic and nemato-
cidal agents.
The control of animal parasites is one of the
oldest and most important problems of the animal husbandry
industry. Many types of parasites afflict virtually
all species of animals. Most animals are afflicted by
free-flying parasites such as flies, crawling ectoparasites
such as lice and mites, burrowing parasites such as bots
ana grubs, and by microscopic endoparasites such as
coccidia, as well as by larger endoparasites such as worms.
Thus, the control of parasites even in a single host species
is a complex and many-sided problem.
The insect and acarina parasites which consume
living tissues of a host animal are particularly harmful.
The group includes parasites of all the economic animals,
including ruminant and monogastric mammals and poultry, and
of companion animals such as dogs as well.
Many methods of control of such parasites have been
tried. The screwworm has been practically eradicated in
Florida by the release of great numbers of sterile male
blowflies. The method obviously is applicable only to an
easily isolated area. The free-flying insects are usually
controlled by routine methods such as air-dispersed and contact
insecticides and fly traps. The skin-inhabiting, crawling
parasites are usually controlled by dipping, drenching, or
spraying the animals with appropriate parasiticides.
~06Q459
Some progress has been made in the systemic
control of some parasites, particularly those which
burrow in or migrate through the host animal. Systemic
control of animal parasites is accomplished by absorbing
a parasiticide in the bloodstream or other tissues of
the host animal. Parasites which eat or come into contact
with the parasiticide-containing tissue are killed, either
by ingestion or contact. A few phosphate, phophoramidate,
and phosphorothioate insecticides and acaricides have been
found to be sufficiently nontoxic to be used systemically
in animals.
Rumanowski, U.S. Patent No. 3,557,211, discloses
N,N-bis(acetyl)-o-phenylenediamines which are useful for
the control of plants, insects and fungi.
It is one of the objects of this invention to provide
compounds whiCh are effective systemic parasiticides.
The present invention is directed to novel
ring-substituted N-~2,2-difluoroalkanoyl)-_-phenylene-
diamine compounds of the formulae:
R3 ~ NH-R
(I) ~ NH-R
R4 ~
R ~ O
NH-R
R5 ~ NH_
n ~ NH-R
(III)R6 - ~ H_R2
wherein
R is a 2,2-difluoroalkanoyl radical of the
formula - C-CF2-Y, in which Y is hydrogen, chlorine, fluorine,
~3--
difluoromethyl, perfluoroalkyl of Cl-C6, or a radical of
the formula
C C H
Z n
in which each Z independently is hydrogen or halogen
and n is O or l;
Rl is
hydrogen,
a radical of the formula-C-O-Yl in which
yl is Cl-C4 alkyl or phenyl,
benzoyl, ~:
furoyl,
naphthoyl, or
substituted benzoyl of the formula
`` ~060~59
o ~ Z'p
----
\~ Z~lq ~
in which each Z' independently iæ halo or nitro, Z"is Cl-C4 alkyl or Cl-C4 alkoxy, p is 0, l, or 2, q is
o or l, and the sum of p and q is l-3; :.
R2 is ;
R
Rl
Cl-Ca alkanoyl,
C3-C4 alkenogl, -
C3- C4 alkynoyl,
halogenated C2-C4 alkanoyl beari~g on any :~
position or positions one or more halogen atoms, each
lndependéntly selected~ sub~ect to the limitation that
the alpha position bear at least one substituent moiety
selected from the group consisting of hydragen and
~: . halogen of atomic weight from 35 to 127, both inclusi~e; ;~-
~ 20 ~ each R3 independentlY is halogen;
:. R4 is nitro;
R5 is trifluoromethyl, difluoromethyl, or
difluorochloromethyl, and in compounds of formula (II),
R and R5 are meta to one another;
: R~ i8 Cl-C4 alkglsulfonyl and i8 located at
the:4 or 5 pos1t~on, and any R4 group is meta to R~;
m 1s ~rom 0-4;
:~ : n is 0 or l; and in compound~ of formula (I),
the sum of m and n is an integer of from 1-4;
: ` :
.
- .
X-3277~ ` _5_
'.
i ,. . .. . . :: . . . . . . . . . .
10~0~59
subject to the further limitation that where
Rl or R2 is hydrogen, the ring position ortho to the
-NH-Rl or -NH-R2 ~roup bears one of the designated R3,
R4 or R5 moieties.
The compounds of formulae I, II and III are
prepared by introduction Or the characteristic 2,2-
difluoroalkanoyl group into the appropriate corres-
ponding diamine starting materials. Introduction of
this group can be achieved by any of numerous available
acylation reactions, employing any of several types of
acylating agents o~ the formula
(IV) H0C-CF2-YJ
wherein Y is de~ined as hereinbefore, or the active
derlvatlve thereof. The identity of the acylating
agent is not critlcal; sultable acylating agents include
the 2,2~difluoroalkanoyl halides:
(V) halo C - CFz - Y ;
and the 2,2-difluoroalkanolc anhydrides:
'S~ -
(VI) o - C CF2 Y 2
wherein Y is de~ined as hereinbefore. The diamine
starting materials with which thea~ylation reaction is
carried out will vary.
Thus, a process for the preparation of the
compounds of formulae I, II and III comprises acylating
a compound selected from the group consisting o~ the
compounds of the formulae:
X-3277B -6-
~ .
106~459 ~ ~
R 3
~ NH2
(VII) ~ NH-R
R4n
R4
(VIII) ~ NH-Rl ;~
Rs
Rn
~ NH2
(IX) ~ ~ NH-R2
R ~ -~ .
wherein the varlous symbols are derined as hereinbefore~
wlth an acylating agent of the formula
(IV) H0~-CF2-Y
wherein Y i8 defined as abo~e or the active derivati~e
thereof.
In the instance of the com~ound~ Or formulae
I, II and III wherein R is hydrogen or wherein R2 is
either hydrogen or the æame moiety as is represented
by R, the starting diamine is a compound of one of the
following formulae:
. Rm3
NH2
(X) ~ NNa
Rn
.
: X-3277B . -7-
iO~0459
R~
(XI) ~ NH2
~NH2
R5
Rn4 `.
(XII) R~ ~ NH2
and either one acyl group is introduced (leaving Rl or
R equal to hydrogen~ or two identical acyl groups are :
introduced (R and R are -C-CF2-Y).
Where, on the other hand, R is any other
moiety than hydrogen and R2 18 any other moiety than
hydrogen or the same 2,2-di~luoroalkanoyl moiety as ~8
represented by R, the appropriate diamine starting
material is a compound already bearing the desir~d R
or R moiety of the formulae: -
Rm3
(XIII) ` ~ NH2
NH-R
Rn
: ~ . R~
NHz
(XIV) . ~ NH-R
,s
R~
(XV ~ Re~NH2
.
: X-3277B -8-
~ ' . .
: :
`- 10ti0459
wherein the symbols are defined as hereinbefore, and the
characteristic R group is similarly introduced by acylation.
It is noted that the R2 group can be a 2,2-difluoroalkanoyl
group different from that represented by R, in which
instance the groups are introduced sequentially.
While the synthetic routes described foregoing
are convenient and preferred, yet other routes can be
utilized. Thus, for example, in the instance where Rl is
an acyl group, the Rl group is conveniently introduced in ~`
some instances after the R has already been introduced.
However, because of the activating effect on acylation of
the alpha fluorine atoms, it is generally preferred that
groups other than the 2,2-difluoroalkanoyl moiety already
be present when this group is introduced. In the instance
where R is formyl, the acylation is conducted with a mixed
anhydride of acetic and formic acid. Alternately, other
acylating agents by which formyl groups are introduced can
be used.
The preparation of amides by the acylating of
corresponding amines with various acylating agents is a
known synthetic method. The present preparations are conducted
in accordance with the known procedures for effecting this
method. Thus, where the acylating agent is an anhydride,
the reaction is conveniently conducted at room te~perature;
solvent, which can be excess anhydride, except in the case of
amides where Rl or R2 is hydrogen, can be utilized. Where
an acyl
1~045g
halide is employed as acylating agent, the reaction
i~ necessarily conducted in the presence of a h~drogen
halide acceptor and preferably in the presence of an
inert sol~ent, and the reaction mixture is preferably
cooled, such as to temperatures of 0-10C. In the case
of either acylating agent, the product is separated ln
conventional procedures, and can be purified if desired>
likewise in con~entional procedures.
For the sake of unirormity, starting materials
and products herein are named, where possible, as o-
phenylenediamines. In accordance with common nomen-
clature practice, the identification of ~arious sub-
stituent positions i8 as follows:
(Nl )
(N2 ~
where either nitrogen atom bears an alkanoyl or other
(R, Rl, R2~ substituent, the ring position numbers are
identified as prime numbers to distingulsh them from
~; numbers o~ positions on the R, Rl, or R2 substituent.
In the foregoing definition of the compounds
of ~ormulae I, II and III, as generally in the present
;~ ~pecification and claims, each of the terms "halo" and
"halogen," when unqualified but as used both alone and
in the composite term "halogenated alkanoyl," designates
bromine, chlorine, fluorine, or iodine~ only.
An e~sential and distingui6hing structural
feature of the compounds of formulae I, II and III is
X-3277B -10-
iO459
the 2,2-difluoroalkanoyl-radical (R); representatiYe of
such radicals include the following:
difluoroacetyl
trifluoroacetyl
difluorochloroacetyl -
pentafluoropropionyl
heptafluorobutyryl
nona- fluoro~aleryl
2,2,3,3-tetrafluoropropionyl
undecafluorohexanoyl
trideca~luoroheptanoyl
pentadecafluorooctanoyl
2,2-difluoroproplonyl
2~2-difluorobutyryl
2~2-di n uoro-3-bromopropionyl
2,2-di~luoro-3-chloropropionyl
2,2-difluoro-3,4-dichlorobutyryl
2~2-difluoro-4-bromobutyryl
2,2,3-txi~luoropropionyl
2,2,3-trifluorobutyryl
~: 2,2,3,4-tetrafluorobutyryl
2,2-difluoro-3-bromo-4-chlorobutyryl
Preferred R groups are trifluoroacetyl, difluoroacetyl,
difluorochloroacetyl, and 2,2,3,3-tetrafluoropropionyl.
The starting materials to be employed in
accordance with the preæent invention are prepared by
known procedures, and some of them are com~ercially
available. Those starting materials which are of the
formula
X-3277B -11-
lObiQ~S9
4 ~ NH2 ~ N~2
Rn ~LNH2 ~NH2 RB~NH2
X XI XII
are prepared by a plurality of synthetic steps as are
necessary to introduce the required moieties. Most
conveniently, one or both of the NH2 groups are intro-
duced by conversion of a halo group. Also, the amino
group or groups can be introduced by nitration and
subsequent reduction. These various synthetic steps
are generally and most conveniently carried out with
starting materials already bearing the requisite R3,
R4, R5 and R~ moieties. However, it is sometimes
preferred that these substituents, where, e.g., nitro
or halo, be introduced simultaneously with the synthetic
steps leading to the introduction of the amino groups.
Thus, for example, where the diamine is
tetrasubstituted, the corresponding tetrasubstituted
benzene is nitrated at each of the remaining ortho
positions and the nitro groups then reduced. A 3-
nitro-5-substituted diamine where the substituent is
alkylsulfonyl is readily prepared by nitrating
a 5-substituted-2-hydroxynitrobenzene to introduce a
3-nitro group, followed by conversion of the hydroxy
group to a chloro, amination, and selective reduction.
Those of the compounds of formula I or II
wherein R2 i~ a moiety other than hydrogen or the same
X-3277B -12-
1060459
acyl moiety as R generally are prepared from diamine
starting materials already bearing the requlsite R
moiety These starting materials are themselves
prepared from the corresponding diamine starting
materials described above, by reaction with an appro-
priate acyl ha ide or, in the instance of Rl or R2
representing -C-Y'~ with an appropriate loweralkyl or
phenyl halo~ormate. Alternately, however, these
starting materials can be prepared from o-nitroanilines:
Rm
f~ NO2
I~NH2
h R4
f R4 . .
~02
~liH2
R5
R
. R~ ~ N2
. by. acylation and subsequent reduction~ both in pro-
! . cedure6 well known in the prior art.
, , .
, .
X-3277B -13-
-- . . .
1060459
All o~ the compounds of formulae I, II, and
III are adapted to be employed as herbicides. These
compounds can be utilized to achieve broad herbicidal
action; hence, in its broadest sense, the present
invention is directed to a process Or applying to a
- plant part, which can be a stem, leaf, flower, fruit,
root or seed or other similar reproductive units Or a
plant, a growth-inhibiting amount o~ one of the ring-
substituted (N-2,2-difluoroalkanoyl)-o-phenylenediamine
compounds of formulae I, II or III. However, these
compounds can also be utilized to take advantage of
Relective patterns of herbicidal activity. As will be -
evident to those skilled in the art, a mixture of more
thàn one of the compounds can also be employed to
achieve herbicidal action. When employing a mixture~
an appropriate reduction should be made in the amount
Or each individual compound sb that the mixture pro-
vides only the desired herbicidal e~fect.
It is not critical to the herbicldal utility
of the compounds that complete destruction o~ undesir-
able vegetation be obtained, it being adequate ir the
growth of the unwanted vegetation is merely inhibited.
Especially where selective action is sought, inhibitlon
falling short of actual killing is adequate, partlcularly
when combined with naturally occurring conditions such ~ -
as limited moisture which more adversely affects the
vegetation selectively inhibited than the crop plant.
~ The compounds of formulae I, II, and III are
suited to a wide variety of herbicidal application~.
.
X-3277B
10~ 459
Thus, for example at rates which evoke the selective
action ~f the compounds, which rates are deflned more
completel~ hereinbelow, the compounds can be used as
selective herbicides in crop plants, such as, for
example, cotton, corn, sorghum and soybeans. In such
use, application can be made preemergent to both crops
and weeds, or, preferably by means of a directed spray
application technique~ postemergent to the crop plant
but both preemergent and postemergent to the weeds.
In another application, the compounds of
formulae I, II and III can be used to give broad
herbicidal action on non-crop land, including inter-
mittently non-crop strips of contour-farmed land For
such usage on so-called fallow land, application can be
made in spring to suppress vegetative growth until a
fall or following spring planting, or in the fall to
suppress vegetative growth until a spring or following
fall planting. ~urthermore, in another applicatlon,
the compounds can be utilized to control weeds in tree
crop plantings, such as plantings of the various citrus
trees. In all of these various applications, and yet
others for which the compounds are suited, another ad-
vantage is that the compounds need not be disced into
the soil being treated, it being adequate if one of the
compounds, or a formulation containing one of the com-
pounds, is merely spread onto the top ~urface. However,
where desired or convenient, the compounds can be
disced into, or otherwise mechanically mixed with the
soil. In addition to the foregoing terrestrial em-
bodiments, the present compounds can also be utilized
X-3277B -15-
1060~59
as aquatic herbicides.
The use of the compounds of formulae I, II
or III as a herbicide can in some instances be carried
out with unmodified compound; however, for good results,
it i8 generally necessary that the compound be employed
in modified form, that is, as one component of a com-
position ~ormulated to implement the plant growth-
inhibiting effects. Thus, for example, the aCtiYe
agent can be mixed with water or other liquid or
liquids, preferably aided by the usage of a surface
active agent. The active agent can also be incorpor-
ated on a finely divided solld, which can be a surface
active substance, to yield a wettable powder, which can
subsequently be dispersed in water or other liquid, or
incorporated as part of a dust whlch can be applied
directly. Other ways Or preparing formulations are
known in the art and can be employed for these compounds.
The exact amount of the active agent employed
is not critical and will vary, depending upon the type
of growth-inhibiting effect desired, the identity of
the plants concerned, the particular active agent
used, and weather conditions. In general, a broad
growth-inhibiting effect is obtained with rates of trom
0.5 to 20 pounds or more of active agent per acre, and
such rates are suitable and effective forcontrol of
vegetative growth on fallow land. When it is desired
to obtain a selective growth-inhibiting effect on weed~
in areas containing crop plants such as corn, soybeans,
and cotton, rates of from 0.5 to 10 pounds generally
give good results. When in the typical mode of
X-3277B -16-
` iO6Q459
operation, the active agent is employed as a composition
comprising the agent, the exact concentration of active
agent in the composition is not critical, except that
the concentration and total amount o~ formulation em-
ployed be adequate to supply the appropriate amount of
active agent on a per acre basis. In general, good
results are obtained when employing formulations con-
taining the active agent in a concentration o~ ~rom 0.5
to 10 percent or higher, in the instance o~ a liquid
formulation; and in a concentration of ~rom 1.0 to 5.0
percent or higher, in the instance of a dust, powder,
granule, or other dry ~ormulation. More concentrated
~ormulations can be prepared and are o~ten preferred in
that they can serve, depending upon the partlcular
application contemplated and the particular concentration,
both as a concentrated ~ormulation for purposes o~ ship-
ment and storage, and as an ultimate treating com-
position. Thus, ~or example, formulations o~ten pre-
~erably contain a surface active agent and the present
active agent, the latter being present in an amount o~
~rom 0.5 to 99.5 percent, by weight, or an inert, ~inely
divided solid and the present active agent, the latter
being present in an amount o~ from 1.0 to 99 percent,
by weight. Such formulations, as indica~ed, can be
employed directly in certain applications, but can also
be diluted and subsequently employed in many other
applications.
Liquid compositions containing the desired
amount o~ active agent are prepared by dissolving the
X-3277B -17-
~60459
substance in an organic liquid or by dispersing the
substance in water with or without the aid of a
suitable surface active dispersing agent such as an
ionic or non-ionic emulsifying agent. Such compositions
can also contain modifying substances which serve as a
"spreader" and "sticker" on plant foliage. Suitable
organic liquid carriers include the agricultural spray
oils and the petroleum distillates 6uch as diesel
fuel, kerosene, fuel oil naphthas, and Stoddard solvent.
Among such liquids, the petroleum distillates are
generally preferred. The aqueous compositions can con-
tain one or more water i~miscible solvents for the
toxicant compound In such compositione~ the carrier
compri6es an aqueous emulsion, e ~., a mixture of water,
emulsifying agent and water immiscible solvent. The
choice of dispersing and emulsifying agent and the amount
thereof employed is dictated by the nature of the com-
position and by the ability of the agent to facilitate
the dispersion of the active agent in the carrier to
produce the desired composition. Dispersing and emul-
si~ying agentæ which can be employed in the compositions
include the condensation proaucts o~ alkylene oxides with
~` phenols and organic acids, alkyl aryl sulfonAtes, poly-oxyalkylene derivatives or sorbitan esters, and complex
ether alcohols. Representative sur~ace active agents
which are suitably employed in implementing the present
invention are identified in U.S. Patents 3~095,299~
- second column, lines 25-36; 2,655,447, column 5; and
2,412,510, columns 4 and 5.
X-3277B -18-
` `
if~ ~ 4 5 9
In the preparation of dust compositlons,
the active lngredlent of formulae I, II~ or III i8
lntimately dispersed in and on a finely di~lded solid
such as clay, talc, chalk, gypsum, lime~tone, vermi-
culite fines, or perlite. In one method Or achie~ing
such dispersion, the flnely divlded carrier is mechani-
cally mixed or ground with the active agent.
Similarly, dust compositions containln2 the
toxicant compounds can be prepared with various Or the
~olid surface active dispersing agents such aB ben-
tonite? fuller' 8 earth, attapulgite and other clays.
Depending upon the proportion~ of ingredient~ t~ese
dust compoeitions can be employed as concentrates and
~ubsequently diluted with additional solid ~urface
active dispersing agents or with chalk, talc, or gyp~um
to obtain the desired amount of active ingredient in a
composition adapted to be employed for the suppression
of the growth of the plants. Also, such du~t composi-
tions can be dispersed in water, with or without the aid
of a dispersing agent, to form spray mixtures.
Formulations containing the present acti~e
agents of formulae I, II or III are often advantageously
further modified by incorporation therein of an effective
amount of a surfactant which facilitates the disper~ion
and spreading of the formulation on the plant leaf
surfaces and the incorporation of the formulatlon by the
plant
The acti~e agent can be dispersed in soil or
other growth media in any convenient fashion. Appli-
cations can be carried out by simply mixing with the
X-3277B -19-
- `
~o~o~s9
media, by applying to the sur~ace of soil and thereafter
dragging or discing into the soil to the desired depth,
or by employing a liquid carrier to accomplish the
penetration and impregnation. The application o~ spray
and dust compositions to the surface of soil, or to
plant part~ or the above ground surfaces of plants can
be carried out by conventional methods, e.g., powder
dusters~ boom and hand sprayers andspray dusters,
whether surface or air-borne. However, while such con-
ventional modes of application can be used~ they are notrequired. It i8 an advantage of the compounds Or
formulae I, II and III that they are active and effecti~e
as herbicide8 when merely placed on the surfàce of the
soil~ without any additional step to as~ist incorporation.
Thus, the compounds are of substantially the same e~fi-
cacy regardless of whether they are applied to the
surface only, or whether they are applied to the surrace
and subsequently disced into the soil.
The distribution of the active agent in soil
can also be accomplished by introducing the agent into
the water employed to irrigate the soil. In such
procedures, the amount of water is varied with the
poroæity and water holding capacity of the soil to
obtain a desired depth of distribution of the agent.
The compounds of formulae I, II and III
exhibit low mammalian toxicity relative to corres-
ponding benzimidazoles. In addition, the compoundg Or
formula I, II, or III may be dispersed as an àerosol
composition containing one or more of the present
active agents as an active compound. Such a com-
X-3271B -20-
~60\4S9
posltlon is prepared according to con~entional methods
wherein the agent is dispersed in a solvent, and the
re~ultant dispersion mixed with a propellant in liquid
state. ~uch variables as the particular agent to be
used and the nature of the vegetation whlch is to be
treated will determine the desirability of the solvent
and concentration of the agent therein. Examples of
suitable solvent~ are water, acetone, isopropanol, and
2-ethoxyethanol.
Sati6factory results are obtained when the
active agent Or formulae I, II or III, or a composltion
compri~ing such acti~e agent, i8 combined with other
agricultural materials intended to be applied to plant~,
plant parts, or their habitats. Such materials include
rertilizers, fungicides, insecticides~ other herbicides,
7' and 80il conditioning agent~.
Various Or the compounds of formulae I, II or
III to be employed as actlve herbicidal agents were
evaluated for preemergent application to various species
of plants. In thi~ evaluation, a soil was prepared
consi~ting of one part masonry sand and one part
~hredded top 80il blended together in a cement mlxer.
One gallon of thi~ soil was placed in a 25 x 35 cm.
galvanized flat and was patted down with a bench brush
until level. A three-row marker was used to make
2 l/2 cm. deep rurrows ii approximately two-~irths Or
the flat. Crop seeds consistlng o~ rour kernels o~
corn, ~l~e cotton seeds, and fiYe soybean seeds were
placed in these furrows. A ~our-row template was then
X-3277B I -21-
.
1060459
placed on the remaining soil and the indicated approximate
numbers of each of the following seeds were planted, one
species to each section: foxtail (millet). 80-100 seeds;
velvetleaf (40-50 seeds); rough pigweed (150-250 seeds);
and large crabgrass (100-150 seeds).
Sufficient soil was added to cover the entire
flat. Thus, the weed seeds were covered to a depth of
about 6 mm. and the crop seeds were covered to a depth
of about 3 cm.
In assaying the effect of the composition as
preemergent herbicides, a flat prepared as above, taken
either on the day of planting or on the next day, was
placed in a chamber equipped with a turntable and an
air exhaust. The herbicidal composition, either a spray-
type emulsion or a wettable powder, was applied to the
flat with a modified DeVilbiss atomizer hooked to an
air source. Twelve and one-half milliliters of the
composition under test were applied to each flat either
on the day of planting or the succeeding day. Injury
ratings and observations as to type of injury were made
eleven to twelve days after treatment. The injury rating
scale used was as follows:
0--no injury
l--slight injury
2--moderate injury
3--severe injury
4--death
When more than one determination was carried out at a
given rate, an average value was calculated for the
-- 2--
~06Q459
in~ury rating. Each compound evaluated was formulated
a~ a spray by one of the following procedure~. In one
test the particular compound was wetted by grindlng ln
a mortar with one part of polyoxyethylene sorbltan
monolaurate. Five hundred parts o~ water were added
slowly to the resultant creamy paste to give an agueous
dispersion with a surfactant concentration of 0.2
percent. This dispersion was entirely satisfactory for
spray application. In a second procedure the compound
was dissolved in one volume o~ acetone, and the acetone
solution was diluted with nineteen volumes o~ water
containing 0.1 percent of polyoxyethylene ~orbitan mono-
laurate.
In the following table setting ~orth the
results o~ the evaluation, column 1 gives the name o~
the compound under test; column 2, the rate in pounds
per acre at which the compound was applied to the test
flat; and the remaining columns~ the in~ury to the
particular plant seeds or seedlings as measured by the
~oregoing scale.
X-3277~ -23-
06~4S9
a ,1 ~ r~ ~ ~.
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X N N ~ ~ ~1~ N
14
b ~ ~ :1- ~t
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V ~ ~ ~ ~ ~N ~ CU ..
a~ a~ l
h a o ,1 o~ N I ~1 0 0
~ ~q , .:
h ;~
H O
~ h o o o ,~ o , ,~ o ,~
El ~
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b~ ~ ,
h ,1 ~1 ~1 0 ,~ O O O
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H u a~ a~ ao CD 0 ~ CU ~1
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. .
h I O I a
~i O o _I I h _I r-l H 0 ~ I 1/~ 0 0
h~l ~ h 01 0 h h h h ~: Id I h ~
,s~ ~ O rl h^ o 0
~ 0 o a ~1 ~ 0 0 ~
U ~d 0 U h ~rl q-l 0 ,s:~ U r1 1~ 0 ~rl
l~J h rl ~J O E3 rl ~3 P
O ~ ~:1 0 ~1 0 h ~ I O rl ~ I O -1
h 0 al h ~ ~ ~ ~ ol h h 0 I~-rl h ~
O ~ 1:~ 0 c~ - I O
:~ ~ a~ a~ 0 ~ o ~ ~
,~ - 01
~ q~ ~O h q~ u~ a~ ~^ ~ 0 q~ h w Pll~ 1 0
:~ ~ o I
O h - a~ h O h OJ h O ~-1 h 0 0 CU h O
E~ l h ~ æ ~ ~ ~ E~ h .c ~ o h
~3 ~ 0 ~1
: o ~ ol ~ a~ CU5 ~ a ol 's'z
X-3277:B -2)1-
1060459
Representative compounds of formula I, II, or
III were evaluated for postemergent applicatio~ to
plants including corn and several weed species. The
evaluation was carried out in accordance with the
previous test procedures except that the test solutions
were applied about 9-12 days after the preparation and
seeding of the flats. The results are as set forth in
the following table:
X-~277B -25-
~060~s9 ` `:
~:
~:
::~
::
~l
X ~ ~'
`::
~ p~ ~ ~:
E~ : '
~ ~ :
~ h
H 0 ~3 ~ ~ ~ :1 ,$ ~ ~ :1 .:t ~ :t
li!l ~ h .
~ O
~ ~ ~' ~
a ~o ~ ,~ N ~
.
~; a~
h
h C~
oq c~ ~ CU ~ ~ CU~ ~J
~: H ;~
~: I I I ~ . ~. '
0~10 ~ I ~ ..
~: ~ . h ~b ~3 ,I h I
- ~ d ~ I ~ 0
,: : ~ ~ ~ O I
h- 0
ol o Ir~ ,l ~.
~ ol~ R~ o I ~1 0 ~
H H~I H h .-1 ~ h 0
.~ 0 ~d
,1 0 R ~ ~ I
o a~ 1 0 1 ol
~ ~ o Eo~aO~ 1
~: ~ hh 01 ~ ~ l ~ I h
O O Q~ O I
o U~ ,l
, 0
R q~ ~ q ~ m ~ q) cu ~ ~ 0
I I 0 _~ ~. o o
. O h b ~rJ h ~ ~ E3 h N
Pl E~ --p, o
E3 ~ ` 1 0 1 0 :~
. O rl - R l - rl - .q rl h ~1 ~rl
C) ~ Z ~
X- 3277~ - 26-
1(~6Q4S9
N2-(2,2,3,3-Tetrafluoropropionyl)-Nl-methoxy-
carbonyl-3'-nitro-5'-trifluoromethyl-o-phenylenediamine
was evaluated as a postemergent herbicide. The e~alu-
ation was carried out in accordance with the test pro-
cedures de 8 cribed hereinbefore, but with a 8 ingle,
higher application rate (15 pounds per acre~ and with
different species (tomato, crabgrass, pigweed). The
specified compound gave a complete kill of each Or the
named specieR. The above de~cribed herbic~dal .compounds
can be formulated and employed with known herbicides of
other classes. The ratio of the individual components ..
of such composit1ons to one another is not critical;
all ratios provide compositions that have userul plant
growth alterlng properties. However, generally pre-
~erred compositions are those ~hereln a ~ubstantial
portion of each component is present--such as compo-
sition~ wherein the ratio of the components ranges from
1:10 to 10:1, especially from 1:5 to 5:1.
Known herbicides with which the compounds of
~ormul~ I, II or III are preferably combined include:
N,N-di-n-propyl-2,6-dinitro-4-(trifluoromethyl)
aniline,
N,N-di-n-propyl-2,6-dinitro-4-methylaniline~ -
::~; N-ethyl-N-butyl-2,6-dinitro-4-(trifluoromethyl)
aniline,
N,N-di-n-propyl-2,6-dinitro-4-(methylsulfonyl~
:~ : aniline,
N,N-di-n-propyl-2,6-dinitro-4-sulfamoylaniline,
N,N- al- _- propyl-2~6-dinitro-4-isopropylanil~ne~
.
X-3277B , -27-
1(1604S9 :
N,N-di-n-propyl-2~6-dinitro-4-tert-butylaniline~
and
N,N-bis(2-chloroethyl~-2,6-dinitro-4-methylaniline.
These possible combinations are exempllfied
by the following procedure:
The combination Or Nl-(pentafluoropropionyl)-
3'-nitro-5'-(tri~luoromethyl~-o-phenylened~amine and
N,N-di-n-propyl-2,6-dinitro-4-(trlfluoro~nethyl)aniline
was evaluated for preemergent application, employing
~arious species Or plants.
A soil was prepared consisting o~ one part
masonry sand and one part shredded top soil blended
together in a cement mixer. one gallon of thls ~oll
~a~ then placed in a 21 5 x 31 5 cm. gal~anized ~lat and
was patted down with a bench brush until le~el Rows
were marked, and seeds planted, one species to a row,
except that in the case o~ the mixture, the mixture was
,.~ . . .
likewiRe seeded in one row The ~pecies employed were
cotton (two separate rows), morning glory (I~omea
~ 20 ~urpurea), foxtail millet, ~imsonweed, velvetleaf, and
a mixture o~ ~ickle pod, pigweed, cypressvine morning
glory (I~omea quamoclit), and Crotolaria.
:: ~
A treated cover soil was then prepared. The
compounds were separately formulated by suspending each
in a 1:1 solution of acetone and ethanol containlng a
small amount of a blend of two sulronate-nonionic sur-
factants. Each suspension was then further diluted
:
serially with an aqueous solut~on of the same blend Or
surractants--to prepare a plurality of aqueous treatlng
X-3277B -28-
.
~. . . . . . .
1060459
solutions containing the respective compounds in various
concentrations, in addition to the blend of eurfactants
uniformly in a total concentration of 0.55 percent, and
the acetone and ethanol uniformly each in a concentration
of 4.15 percent Treating solution containlng each of
the compounds were sprayed onto a portion Or soil of the
same type as described above, while rotating ln a ceme~t
mixer. The rotation was continued for 5-7 minutes.
Each portion of soil so treated was then spread over a
flat to a depth of three-eighths inch.
Another flat was prepared and seeded in like
manner, except that the cover soil was left u~treated
to serve as a control All ~lats were held for thlr-
teen days under normal greenhouse condltions, at which
time ln~ury ratings and observations as to type of
in~ury were made. The in~ury rating ~cale used was as
follows:
0-----no in~ury
1-3---slight in~ury
4-6---moderate in~ury
7-9---severe in~ury
lO----death
B-----burned
N-----no germination
R-----reduced germination
S-----stunting
The following table reports the results of the evalu-
ation of the treated flats. In the control flats,
there were healthy stands of each of the test species.
X-3277B -29-
10604S9
~ '.'
H O O O N 1~ 0 0 ~
:~
a~
P; tq
V~
~q ~; P; ~ P; p: O ~r;
.~ CO ~ ~ CO o~
~ :'
o Cq ~q
m m cQ c
~o o o o ~ o ~ ~ ' ''.
. ',.
~ ~ ~ .
~ ~r; v
a) ~ CQ _l .. .
; ~ h
m ~ m ~ .
O o O cO o~ N ~t 0~ ~ A
01
I ~,
H r-l ~ ~ ~rl
~ ~z; cq k ~; ~a!; 5!; Z S; ~ H
~ ~ O ~; O O O O O O ~ ~ .
5C ~ ,~ o 0
~! ~ h
, ~
b~
h E~
~rl h ~ 2; ~ O
~ o ~ m m o a~ m m o _ h
h N N ~ H N ~0 ~ H
O 'I
rl
a h h
O ~q ~ -- .
. ~ ~o O O N ~ O O O O
. ~ h
~: . . . ~ a
- ~ ~
P~ ~o
. . . . . o ..
` i~ ~ ~ ~ N
: ~ ~ -I ~ ~ O ~1
CO ~ O
~I ~I,$ rl h
h~ ~ p,
: ~ : ~ c~ ~ m ~ m m ~ ~ .
.~ m ~ al
n~ ~ .~ m ~ .
rl
rd~ ~ ~ ~ ~
' ~ ~ ~ ~ 1
O ~ ,1 ~ .
H H H N H H H N
O ~1 ~
c~ ¢ ¢ ¢ ¢ ~¢ ¢ ¢ ~ ¢ m
X- 3277B ~ 30-
~()60459
~ ike results are achie~ed when combining
Nl-(pentafluoropropionyl~-3'-nitro-5'-(trifluoromethyl)-
o-phenylenediamine or other of the novel compounds Or
formula I, II, or III with other of the dinitroaniline
compounds identified hereinabove. In general, good
results are obtained when the combinations are employed
to supply from 0.5 to 8.o pounds of the N-(2,2-di-
fluoroalkanoyl~-o-phenylenediamine per acre, and from
0.25 to 2.50 pounds of the dinitroaniline per acre.
Essentially the same results as those re-
ported in ~oregolng test~ are obtained ~hen e~aluating
the iollowing other representative compounds of formula
I, II or III:
Nl-Propionyl-NZ-(2,2-diiluoro-~-iodopropiongl~-
5'-(_ec-~utyl~ulfonyl~-o-phenylenediamine
N -Triiluoroacetyl-N2-~-toluoyl-5',6'-di-
chloro-o-phenylenediamine
: N -Diiluorochloroacetyl-N2-hexanoyl-5'-
(n-propyl 8ul ionyl~ phenylenediamine
N -(3-Bromopropionyl~-N2-triiluoroacetyl-5'- .:
(ethylsulionyl~-o-phenylenediamine : :
N -(2,2-Difluoro-3-bromopropionyl~-N2-(2- :
chloro-4-tert-butylbenzoyl~-3'-nitro-5'-triiluoromethyl-
o-phenylenediamine
N -Triflu-oroacetyl-NZ-(methoxycarbonyl)-5',
6'-di~luoro-o-phenylenediamine
N -Difluorochloroacetyl-N2-(phenoxycarbonyl)-
; 3'-nitro-5'-(difluoromethyl~-o-phenylenediamine
: X-3277B -31-
1(~60459
N -Difluoroacetyl-N2-(~;~4-dichlorobenzoyl)-
4'-chloro-o-phenylenediamine
N -Pentafluoropropionyl-N -(5-bromo-m-toluoyl)-
3',~',5',6'-tetrachloro-o-phenylenediamine .
N -Heptafluorobutyryl-N2-(sec-butoxycarbonyl)-
4'-bromo-o-phenylenediamine
Nl-Iodoacetyl-N2-trifluoroacetyl-5'-(methyl-
sulfonyl)-o-phenylenediamine
Nl-Trifluoroacetyl-N2-naphthoyl-3'-nitro-
5'-tri~luoromethyl-o-phenylenediamine
N -Trifluoroacetyl-N2-(~-n-butoxybenzoyl)-4'-
tri~luoromethyl-6'-nitro-o-phenylenediamine
Nl-Trifluoroacetyl-N2-(~-nitrobenzoyl)-4'-
trifluoromethyl-6'-nitro-o-phenylenediamine
Nl-Tri~luoroa¢etyl-N2-(2,4-dichloro-6-methoxy-
benzoyl)-6'-nitro-o-phenylenedlamine
Nl-Heptafluorobutyryl-3'-nitro-5'-trirluoro- .
~: methyl-o-phenylenediamine . .
Nl-Pentarluoropropionyl-3'-nitro-5'-tri-
~luoromethyl-o-phenylenediamine
N -Trifluoroacetyl-NZ-methoxycarbonyl-4'-
trlfluoromethyl-6'-nitro-o-phenylenediamine
N -Pentadecafluorooctanoyl-3'-nitro-5'-
: trifluoromethyl-o-phenylenediamine
Nl-Trifluoroacetyl-N2-benzoyl-3'-trirluoro-
methyl-5'-nitro-o-phenylenediamine
Nl-Trifluoroacetyl-N2-naphthoyl-4'-trifluoro-
methyl-6'-nitro-o-phenylenediamine
~ , ' '
:, ~' ', . ;
: X-32773 -32-
: ~ :
1060~S9
N -Trifluoroacetyl-N2-trichloroacetyl-3'-
nitro-5'-(methylsulfonyl)-o-phenylenediamine
N -Pentadecafluorooctanoyl- ~-acetyl-4'-
(methylsul~onyl)-o-phenylenediamine
N ,N2-Bis(heptafluorobutyryl)-4'-(methyl-
8ulfonyl)-Q-phenylenediamine
N -Trifluoroacetyl-N2-acryloyl-4'-(methyl-
sulfonyl)-o-phenylenediamine
Nl-Trifluoroacetyl-N2-propioloyl-4'-(methyl-
æulfonyl)-o-phenylenediamine
Nl-Trifluoroacetyl-N2-benzoyl-4'-(ethyl-
sulfonyl)-6'-nitro-o-phenylenediamine
Nl-pentafluoropropionyl-NZ-naphthoyl-4'-
~methylsulfonyl~-Q-phenylenediamine
Nl-Difluoroacetyl-N2-methoxycarbonyl-4'-
(methylsulfonyl~-o-phenylenediamine
N -Heptafluorobutyryl-N2-~-toluoyl-4'-
(methylsulfonyl)-6'-nitro-o-phenylenediamine
N -Tri~luoroacetyl-NZ-benzoyl-4',5'-dichloro-
o-phenylenediamine
N -Trifluoroacetyl-N2-naphthoyl-4'-nitro-o-
phenylenediamine
Nl-Trifluoroacetyl-N2-furoyl-5'-(methyl-
: sulfonyl~-o-phenylenediamine
N -Chlorodifluoroacetyl-N -furoyl-4',5'-
dichloro-Q-phenylenediamine
The compounds of formulae I and II also
exhibit insecticidal and arachnicidal activity. This
activity is most pronounced among compound~ of formula
X-3277B -33-
106Q459
II. These compounds are useful for the control of insect
and arachnid pests and, with proper selectlon of rates
to avoid phytotoxicity, can be used for the control of
those insect and arachnid pests found on the roots or
aerial portion of plants. These compounds are active,
~or example, against such arachnids as red spider mlte,
citrus mite, two-spotted spider mite, Pacific mite,
clover mite, fowl mite, various species Or ticks, and
various species o~ spiders. The compounds of this sub-
genus are also active against insects of the variousorders including Mexican bean beetle, boll weev~l, corn
rootworm, cereal leaf beetle, flea beetles, borers,
~olorado potato beetle, grain beetles, alfalfa weevil,
carpet beetle, con~used ~lour beetle, powder post
beetle, wireworms, rice weevil, rose beetle~ plum
curculio, white grubs~ melon aphid, rose aphid~ white
fly, grain aphid, corn leaf aphid, pea aphid, mealybugs,
scales, leafhoppers, citrus aphid, spotted alfal~a aphid,
green peach aphid,~bean aphid, milkweed bug, tarnished
plant bug, box elder bug, bed bug, squash bug, chinch
bug, house fly, yellow fever mosquito, stable fly, horn
fly, cabbage maggot, carrot rust fly, Southern armyworm,
codling moth, cutworm, clothes moth, Indianmeal moth~
leafrollers, corn earworm, European corn borer, cabbage
looper, cotton bollworm, bagworm, sod webworm, fall
armyworm, German cockroach, and American cockroach.
In addition to utilization for the control of
pests on plants, the compounds of this sub-genus can
also be included in inks, adhesives, soaps, polymerlc
"
X-3277B -34-
. .
10604S9
materials, cutting oils or in oil or latex paint.~. Also,
the products can be distributed in textiles, cellulose
materials, or in grains, or can be employed in the
impregnation of wood and lumber. Additionally, they
can be applied to seeds. In yet other procedures, the
products can be vaporized or sprayed or distributed as
aerosols into the air, or onto surfaces in contact with
the air. In such applications, the compounds manifest
the useful properties hereinbefore described.
The process of using these insecticidal
and arachnicidal compounds comprises contacting an
insect or arachnid with an inactivating amount of one of
the compounds of the present sub-genus. Contactlng c~n
be effected by application of one or more of the pro-
ducts to a habitat of the insect or arachnid. Repre-
sentative habitats include soil~ air, water, food,
vegetation, inert ob~ects, stored matter such as grains,
and other animal organisms. The inactivatlon can be
lethal, immediately, or with delay, or can be a sub-
lethal one in which the inactivated insect or arachnid
is rendered incapable of carrying out one or more of its
normal life processes. Among known insecticides, this
latter situation typical~y prevails when one of the
syætems of the organism, often the nervous system~ ls
seriously dixturbed; however, the precise ~echanism by
which the compounds constituting the present active
agent work is not yet known, and the insecticidal and
arachnicidal effectiveness is not limited by any mode
of operations.
X-3277B _35_
, , ~ ~ - . . ; ~. . .
~(~6~459
The utilization of an inactivating amount o~
one of the compounds of the sub-genus is critical to the
insecticidal and arachnicidal effectiveneæs. The in-
activating amount can sometimes be administered by em-
ploying the compound in unmodified form. Frequently,
however, the desirable insecticidal and arachnicidal
properties of the compounds of the sub-genus can be
utilized only, as in the instance of the herbicidal
properties, when one or more of the compounds is formu-
lated with one or more ad~uvant substances. Reference
is made to the discussion hereinbefore concerning com-
positions and adjuvants. Where the insecticidal and
arachnicidal compound~ of formulae I and II are used
for the control of plant-attacking insects and arach-
nids, it is pre~erred that any ad~uvants be essentiQlly
non-phytotoxic in the formulated composition.
The exact concentration of one or more of
the compounds of the sub-genug in a composition thereof
with one or a plurality of ad~uvants can vary; it is
necessary only that one or more of the products be
present in such amount as to make po3sible the applica-
tion of an inactivating do~age to an insect or arachnid.
- In many sltuations, a composition comprising 0.000001
percent of the active agent is effective for the
~administration of an inactivating amount thereof to
insect and arachnid pest organisms. Compositions having
a higher concentration of active agent, such as a con-
centration of from 0.000001 to 0.5 percent, can of
couræe be employed. In still other operations,
X-3277B -36-
10~0459
compositions containing from 0.5 to 98 percent by
weight of one compound or from 0.5 to 98 percent of a
total of more than one compound, are conveniently em- -
ployed. Such compositions are adapted to be employed
as treating compositions and applied to insects and
arachnids and to their habitats, or to be employed as
concentrates and subsequently diluted with additional -
adJuvant to produce ultimate treating compositions.
one or more of the compounds of the sub-genus or a
composition containing one or more of the compounds is
applied to the pest~ to be controlled directly, or by
mean~ of application to a portion or portions of their
habitat in any convenient manner, for example, by means
of hand dusters or spragers or by simple mixing with
the food to be ingested by the organisms. Application
to the foliage of plants i8 conveniently carried out
with power dusters~ boom sprayers, and fog sprayers.
In such foliar applications, the employed compositions
should not contain any appreciable amounts of any
phytotoxic diluents. In large-scale operatlons, dusts,
or low-volume sprays, can be applled from an airplane.
Also~ the use of compositions comprising one or more of - -
the compounds of the sub-genus, an ad~u~ant, and one
or more biologlcally active materials, such as other
lnsecticides, fungicides, miticides, bacterlcides, and
nematffcides are po~Rible.
Compounds e~aluated for the control of insects
and arachnids, as reported in the following tests, were
for~ulated ln accordance with the following procedure.
.
X-3277B -37-
~ .
,
. . ' .. ' ' ' . . . . . ~ A . .
~(~60459
Initially, 55 grams of a mixture of two nonionlc sul-
fonate emulsifiers were mixed with 1 liter o~ cgclo-
hexanone. Of the resulting mixture, 0.9 milliliter
was subsequently further mixed with 90 milligrams o~ the
sub~ect compound and diluted with distilled water to 90
milliliters, containlng the sub~ect compound at a con-
centration of 1000 parts per million. For evaluation
at lower concentrations, the mixture was further diluted
with a dilution composition consisting o~ 4 liters of
distilled water and a total of 1.8 milliliter Or the same
two nonionic sulfonate emulsifiers.
~ he insecticidal and arachnicidal activity
of the compounds of formulae I and II are illustrated
by the following tests against repre~entative insects
and arachnids.
Mexican Bean Beetle -
E~ilachna varivestis (Coleoptera~
Cuttings of four six-day-old Bountliul snap
bean plants containing two leaves with approximately 5
square inches of leaf surface were placed in water.
~he leaves were ~prayed to wetting with about 5-10 ml.
of a formulation containing a predetermined level of
; the test compound. Half of the formulation was sprayed
~ on the top surface and half on the bottom ~urface Or the
; leaf using a DeVilbiss atomizer at 10 pBi held at a
distance of about 18 inches from the leaf. After the
; leaves had dried, they were cut from the stem and placea
separately in petrL dishe~ Ten third instar, non-
molting Mexican bean beetle larvae grown on Bountirul
,:
X-3277B -38-
. . . . . . .
1(~604S9
snap beans were placed on each leaf. Controls consisted
of two leaves sprayed with 5 ml. of a 500 ppm. formula-
tion of S-(1,2-dicarbethoxyethyl~ 0,0-dimethyl phos-
phorodithioate (reference standard), two leaves sprayed
with the formulation without the active ingredient and
two leaves were held as untreated controls. After 48
hours J a mortality count was made and the amount of
feeding noted. Moribund larvae were countea as dead.
The following toxicity rating scale was used:
10Percent Dead Rating
0-10 0
11-20
~2I-30 2
31-40 3
41-50 4
51-60 5
61-70 6
71-80 7
81-90 8
2091-100 9
The compounds so evaluated, the rates employed?
and the results of the evaluation are as set forth in
. ~,
the following table. Where more than one evaluation
was carried out at a gi~en rate, the result reported
for that rate is an a~erage of the several results.
,, ,
X-~277B _39_
~: :
~: `
.. . .. . . .. . . . . . . .. ... .
iO604S9 ` `~
Lq
,,, ~
0 ,, ..
¢ Q~
a~
.
.. ~.
W
0~ ooooooooooooU~
K~
~ a ~ o~
C~ -.
C~ ~
X . .
X Q~ .,
o ~:
E~ . .
~q
.,~ o o o
I o o o o o o o
¢ ~I O O O O O O O ~ O U~ o U~ ~U
E~ ~ ~ O O u~ O u~ O u~
C~ ~ ~ ~ CU
O h
0
. 0~
a~
a
~ o
: :: I ~: h I "'~
- W ~ ~ ~ -
u~ a ,~ -
, ~ a ~
o ~ I ~ O I
~ a ~ ~ ol
a, aP, ~ q h
01 ~,;
P~ 0~
. ~ ~ . ~ ol o :" ~ h :- `
h ,~: ~ O ~t
a) ~1 o
:` ~ O ~ t.~ o o
h ~ O h b
O ~ h O O
~d ~ O ~ O
~I h
O ~ q~
o " ~ a
h rl _I h rl h O :~.
~3 E~ l h
~ O , .,1 1 1 W ~ ~
,
~ ~ X- 3277B _ 40_
106(~4S9
Southern Armyworm -
Prodenia eridania (Lepidoptera)
Ten uniform Southern armyworm larvae about
1-1.5 cm in length, grown on Henderson lima bean~, were
placed on excized bean leaves in petri dishes. The bean
leaves were obtained and sprayed with the insecticide in
the same way as were the snap bean leaves in the Mexican
bean beetle test. The reference standards in this
instance were leaves sprayed with 5 ml. of 100 ppm. DDT
solution. Mortality counts were made 48 hours after
spraying and again moribund larvae were counted as dead.
Mis~ing larvae which had probably been eaten were
considered alive. The same rating scale was used as in
the Mexican bean beetle test
The compounds 80 eraluated, the rates em-
ployed, and the results of the evaluation are a~ set
forth in the following table. Where more than one -
evaluation was carried out at a given rate, the result
reported for that rate is an average o~ the 8e~eral re~ults
TABLE V
Toxlcity Rating
Rate in Parts Against Southern
N -Difluorochloro- 1000 8.5
acetyl-3'-nitro-5'-
trifluoromethyl-o-
` phenylenediamine
.. .. . . . . _ _ .
Melon Aphid -
A~his ~ossY~ii (Hemiptera)
~ X-3277B 41-
.~ ; .
10604S9
Four blue hubbard squash seeds were planted
per container in vermiculite and the containers watered
from the bottom. A~ter six days, the two weakest plants
were cut of~ and one cotyledon and the primary leaves
removed from each of the two remaining plants. The
remaining cotyledon was in~ested with 100 melon aphids
~rom a stocX colony by pinning the cotyledon against an
aphid-infested squash cotyledon from the colony and
allowing the aphids to trans~er. After transfer, the
colony leaf was removed. Forty-eight hours later~ the ~ -
infested leaves were sprayed to wetting with rormulations
containing graded amounts Or the insecticide using a
DeVilbiss atomizer at 10 psi held at 12-15 inches from
the plant. Controls consist o~ two infested, unsprayed
~quash plants and two in~ested plants 8prayed to wetting
with a formulation containing 100 ppm. Or S-(1,2-dicarb-
ethoxyethyl) 0,0-dimethyl phosphorod1thioate as a
referenoe standard. The mortality was estimated 24
hours after spraying by observation using a 10-power
dissecting microscope. The same rating scale was used
as before
The compounds so evaluated, the rates employed,
and the results of the evaluation are as set forth in
~ .
;~ the ~ollowing table. Where more than one evaluation
was carried out at a given rate, the result reported
for that rato is an average Or the several results.
~ .
,
.
X-3277B -42-
~:
: .
. ~ . .
1060~59i
TABLE VI
Toxicity
Rate in Parts Rating Against
Compound Per Million Melon Aphid
N1-Trifluoroacetyl-3'-1000 9.0
nitro-5'-trifluoro-
methyl-o-phenylene- 500 9.0
diamine
250 9.0
100 8.o
7.0
N -Difluorochloroacetyl- 1000 9.0
3'-nitro-5'-trifluoro-
10 methyl-o-phenylene_ 500 g.o
diamine
250 8-5
100 8.
Nl-Trifluoroacetyl-3'-1000 9.0
trifluoromethyl-5'-nitro-
o-phenylenediamine 500 9,0
250 9~0
: :
Two-Spotted Spider Mite -
TetranYchus urticae (Acarina~
Two-æpotted spi-der mites were raised on green
~- bean plants, then transferred to squash plants. The
squash plants were maintained for two days 80 that the
,- ~
,
infestation was well established. The lnfected squash
plants were then sprayed with a test formulation con-
taining the sub~ect compound as in the preceding test
methodæ. Mortality was determined by estimation 48
~ ~ -
houre after spraying. The same rating scale wa8 u8ed a8
in other test procedures.
The compounds 80 evaluated~ the rates em-
ployed, and the reæultæ of the evaluation are as set
X-3277B -43-
~ .
., , : : .
106Q459
forth in the following table.
TABLE VII
Toxicity Rating
Rate in Part~ Aeainst Two-
CompoundPer Million Spotted S~ider Mite
Nl-Trifluoroacetyl-1000 9.o
3'-nitro-5'-tri-
fluoromethyl-o- 500 g.o
phenylenediamine
250 9.0
100 9- "
5 8.5
Nl-Pentafluoro- 1000 9.0
propionyl-3'-nitro- ::
5'-trifluoromethyl-500 9.0
o-phenylenediamine
250 9- ::
100 9~
5 8-5 ::
Nl-Difluorochloro-1000 9.0
acetyl-3'-nitro-5'-
trifluoromethyl-o-500 g 0
phenylenediamine
250 9-
100 8.o
5 9 `
Nl-Trifluoroacetyl-1000 9.0
~:: 3'-trifluoromethyl-
5'-nitro-o-phenylene-500 9.0
diamine
250 9
' 100 9.0
8.o
: : :
:: :
,,
X-3277B _44_
-
106Q459
Milkweed Bug -
Oncopelitis fasciatus (Hemiptera~
Ten adult milkweed bugs were chilled and placed
in a test cage. The cages containing the bugs were
sprayed with 5 ml. of a test formulation containing a
predetermined amount of the insecticide, using a
DeVilbiss atomizer at lO psi held 33 inches from the top
of the cage. After the cage had been allowed to dry, the
bugs were fed and watered for 48 hours A formulation
containing 500 ppm. of 2-(1,2-dicarbethoxyethyl) 0,0- ;
dimethyl phosphorodithioate was used as a reference
standard and two unsprayed cages were kept as controls.
Mortality counts were made 48 hours a~ter spraylng.
Moribund adult8 were considered dead. The 8~me rati~g
~cale Was employed as be~ore.
The compounds 80 evaluated, the rates employed
and the results of the evaluation are as set forth in
the following table.
TABLE VIII
Toxicity
Rate in Parts Rating Against
Com~ound Per Million Mil~weed Bu~
N -Trifluoroacetyl- lOOO 9.0
3'-nitro-5'-trifluoro-
methyl-o-phenylene- 500 9.0
diamine
250 9-
100 9. 0 .
8 . o
Nl-Difluorochloro- 1000 9.0
acetyl-3'-nitro-5'-
trifluoromethyl-o- 500 g o
phenylenediamine
250 9-
X-3277~ -45-
106Q4S9
TABLE VIII (cont'd)
Toxicity
Rate ln Part6 Rating Against
Com~ound Per Million Milkweed Bu~
Nl-Difluorochloro- 100 9.0
acetyl-3'-nitro-
5'-trifluoromethyl-
o-phenylenediamine
N1-Trifluoroacetyl-3'-1000 9
trifluoromethyl-5'-
nitro-o-phenylene- 500 9.0
diamine
250 9.0
Nl-Heptafluorobutyryl- 1000 9. 0
3'-nitro-5'-trifluoro-
methyl-o-phenylene- 500 g,o
diamine
250 9.0
100 9~
g.o
House Fly -
Musca domestica (Diptera)
Rearing cages containing four-day-old adult
house flies were chilled at 2-4C. for about 1 hour.
One hundred flies were transferred from the rearing cage
to each test cage using a small 8COOp. The caged flies
were kept for 1-2 hours at 21-27C. The cages were
sprayed in the same manner as described for the milkweed
bug with 5 ml. of the test formulation. Two unsprayed
cages were held as controls and two cages were sprayed
with a 50 ppm. DDT formulation as a reference stanaard.
Mortality counts were made 24 hours after spraying. All
flies that did not fly or did not walk up from tke
bottom of the cage were considered moribund. The same
X-3277B -46-
.
~060~s9
rating scale was employed as hereinbefore.
The compounds so evaluated, the rates em-
ployed, and the results o~ the evaluations are as set
~orth in the followine table. Where more than one
evaluation was carried out, the result reported ror that
rate is an average o~ the several results.
. ,..-: :
TABLE IX
Toxicity
Rate in Parts Rating Against
Com~ound Per Million House_Fly
: :.
Nl-Trifluoroacetyl- 1000 9.0
3'-nitro-5'-trifluoro-
methyl-o-phenylene- 500 9.0 ~-
diamine
250 9.0 --
100 . 9~ 0
8.5
N~-Difluorochloro- 500 9.0
acetyl-3'-nitro-5i-
trifluoromethyl-o- 250 9.0
phenylenediamine -
100 9. 0 ':
5 9 0
~~
;~ ~ Boll Weevil -
Anthonomus ~randis (Coleoptera)
The procedure was identical to that employed
for the Mexican bean beetle and the Southern armyworm,
except that 10 adult boll weevils were placed on cotton
leaves that had been dipped into formulations of the
test compounds The same rating scale was used.
~ -
:, .
~ X-3277B -47-
1060459
The compounds so evaluated, the rates -
employed, and the results obtained are as set forth in
the following table. Where more than one evaluation
was carried out, the result reported for that rate is an
a~erage of the several results.
TABLE X
Toxicity
Rate in Parts Rating Against
Com~ound Per Million Boll Weevil _
N -Hepta~luorobutyryl-1000 9.0
3'-nitro-5'-trifluoro- :
methyl-o-phenylene- 500 9.0
diamine
250 9-
100 9- : '
9.0
9.0
Nl-Pentafluoropropionyl- 1000 9.0
3'-nitro-5'-trifluoro-
! methyl-~-phenylene- 500 9.0
d i amine
250 9-
1: ,.
,, ,, 100 9~
5 9
8.5
8.5
Nl-Perfluorooctanoyl-1000 9.0
1~ : 3'-nitro-5'-trifluoro-
'~ methyl-o-phenylene- 500 9.0
diamine
250 9-
100 9-
5 9.0
g.o
, ~ .
X-3277~ -48-
.
:~0459 ~:
Results essentially the same as those ~-:
reported in the above tables are obtained when
evaluating in the same procedures the following compounds:
N -(2,2-Difluoro-3-bromopropionyl)-
N2-(2-chloro-4-tert-butylbenzoyl~-3'-nitro-5'-
trifluoromethyl-o-phenylenediamine
Nl-Difluorochloroacetyl-NZ-(phenoxy- ~
carbonyl)-3'-nitro-5'-difluoromethyl-o-phenylenediamine ~:
Nl-Trifluoroacetyl-N2-naphthoyl-3'-nitro- : ;
5'-trifluoromethyl-o-phenylenediamine
Nl-Trifluoroacetyl-N2-(~-_-butoxybenzoyl)- .
4'-trifluoromethyl-6'-nitro-o-phenylenedia~ine
Nl-Trifluoroacetyl-N2-(~-nitrobenzoyl)-4'- . ~ :
tri~luoromethyl-6'-nitro-o-phenylenedlamine
Nl-Hepta~luorobutyryl-3'-nitro-5'-tri-
~luoromethyl-o-phenylenediamine
N -Pentarluoropropionyl-3'-nitro-5'-tri-
fluoromethyl-o-phenylenediamine
Nl-Trirluoroacetyl-N2-methoxycarbonyl-4'- .-
trifluoromethyl-6'-nitro-o-phenylenediamine
N -Pentadecafluorooctanoyl-3'-nitro-5'-
~; tri~luoromethyl-o-phenylenediamine
; Additionally, the compounds of formula II
are useful parasitlcides for the systemic control of
insects and acarina which feed on living tissues o~
animals. ~hese compounds have the ability to permeate
the living tissues of a host animal to which one o~
the compounds is administered. Insect and acarina
X-3277B -49-
. . . , . . . . .~ .. ... , ~ .. ; . . .. . .
1~)60459
parasites which consume blood or other li~lng ti~sues
of the host animal ingest the compounds with which the
tissue is permeated, and are thereby killed. It is
probable that the blood is the agency through which the
compound i6 dispersed through the host animal, but
parasites such as screwworms, which do not suck blood,
are killed by these compounds, indicating that the
compounds permeate other tissue6 as well as blood.
Some parasites, such as most ticks, ~eed on
living tissues of the host animal during most of the
parasite's life. Other parasites, such as screwworms, ~ -
feed on the host only in the larval stage A third
group of parasites, such as the bloodsucking flies,
feed on animal hosts only in the adult stage. Ad-
ministration of the compounds Or ~ormula II to host
animals kllls parasltes which feed on the living tissues
of thè anima~s, no matter what the life stage o~ the
~eeding parasite.
~ll the ~pecies o~ insect and acarina para-
sites which feed on the living tissues of animals are
killed by the compounds of formula II. The parasipes
which suck the host animal's blood, those which burrow
into and feed on the animal's tissue, and those, like
the larvae o~ the bot flies, which enter a natural
~- ; ori~ice of the host, attach to the mucous membranes~
and feed there~rom are all equally effectively killed.
For the sake of clarity, a number of specific parasites
of various host animals which are controlled by using
these compounds will be mentioned. The parasitiG life
:: :
X-3277B _50_
: .
` ~0604~;9
stage and the means by which it infests the host
animal arc g~ven for each parasite.
Parasites of Horses
horsefly, adult, bloodsucking
stable ~ly, adult, bloodsucking
black fly, adult, bloodsucking
horse sucking louse~ immature, adult,
bloodsucking : -
mange mite, nymph, adult, skin-burrowing
scab mite, adult, skin-eating
common horse bot rly, larva, migrating
in alimentary canal
chin fly~ larva, migrating in alimentary
canal
nose bot ~ly, larra, migrating in alimentary
canal
Parasites o~ Bo~ines
horn fly, adult, bloodsucking
cattle biting louse~ adult, skin-eatlng
cattle bloodsucking louse, nymph, adult,
bloodsucking
; tsetse ~ly, adult, bloodsucking .
stable fly, adult, bloodsucking
horse fly, adult, bloodsucking
cattle follicle mite, adult, skin-burrowing
cattle tick, larva, ngmph, adult, bloodsucking
ear tick? nymph, bloodsucking
Gul~ Coast tick, adult, bloodsucking
.~ Rocky Mountain spotted-fever tick, adult,
30 bloodsucking
X-3277B . -51-
10fà~459
lone star tick, adult, bloodsucking : --
heel fly, larva, migrating through the body
bomb fly, larva, migrating through the body
blowfly, larva, infesting wounds
assassin bug, bloodsucking
Parasites of Swine
hog louse, nymph, adult, bloodsucking
chigoe ~lea, adult, bloodsucking
Parasites of Shee~ and Goats
bloodsucking body lou~e, adult, bloodsucking
bloodsucXing foot louse, adult, bloodsucking
sheep ked, adult, bloodsucking
sheep scab mite, nymph, adult, skin-eatlng
nose ~ly~ larva~ migratlng in the sinuses
greenbottle fly, larvaJ infesting wouDds
black blowfly, larva, infesting wounds
secondary screwworm, larva, infesting wounds
Parasites o~ Poultr~
: bed bug~ nymph~ adult, bloodsucking
~ : 20 Southern chicken flea, adult, bloodsucking :
.~ fowl tick, nymph, adult, bloodsucking
chicken mite, nymph, adult, bloodsucking :- -
scaly-leg mite, adult, skin-burrowlng
depluming mlte, adult, skln-burrowlng
Paraæiteæ o~ Dogs
horse fly, adult, bloodsucking
~ : stable fly, adult, bloodsucking
:~ ~ mange mlte, nymph, adult, skln-burrowing
dog follicle mite,.adult, burrowing in hair
follioles
:~ X-~277B 52-
~ .
~, . , . " . . ~ , . ~ - . . .
10~;0459
flea, adult, blooasucking
It will be understood that the parasites
mentioned above are not confined to the single host
animal with which each is here identified. Most para-
sites inhabit various hosts, although each parasite
has a favorite host. For example~ the mange mite attacks
at least horses, hogs, mules, humans, dogs, cats, foxes?
rabbits, sheep, and cattle. Horseflies freely attack
horses, mules, cattle, hogs, dogs, and most other
animals. Use of the compound~ of formula II kllls
parasite~ of the types described above growing in the
host animals mentioned above, and in other host an~imal~
as well. For example, these compounds are effective in
cats, goats, camels, and zoo animals.
The host animals in which the~e compounds are
preferably used are dogs, bovines, sheep, or horses for
the control of ticks, ~leas, flies, or screwworms.
The time, manner, and rates at which the
compound3 are effecti~ely administered may be ~aried
over a wide range. Detailed explanation of the ways in
which these compounds are used w111 be given herein-
below.
The compounds are administered to the animals
at rates from about 1 to about 100 mg./kg The best
rate for killing a given parasite infesting a given
animal must be determined individually, but ~t will be
found that in most cases the optimum rate is within the
preferred range of from about 2.5 to 50 mg./kg. The
optimum rate for a given instance depends on such
; : ,
~ X-3277B _53_
.
.
:
iO~;O~S9
factors as the health of the animal to be treated, the
susceptibility of the parasite of primary concern, the
expen~e which can be borne by the animal~ and the degree
o~ control desired. Lower rates are safer ~or the host
animal, less expensive, and often easier to adminlster,
but are likely to give incomplete or minimu~ control Or
the parasite so that reinfestation may occur. On the
other hand, higher rates of administration give more
complete control of the parasites, but are more ex-
pensi~e and may impose a stress on the treated animals.
The compounds of formula II are efrectivewhen administered at any time of year to animals of any
age. It is possible to administer these compounds to
the anlmal8 contlnuou81y, as by constant feed~ng o~ a
diet which contains one of the compounds, and thus assure
thàt all parasites which contact the treated animal wlll
be killed. Such admini~tration is by no means economical, ~`
and it will usually be found best to administer the
compounds at such times as to give the best return of
parasite control ror the compound expended. Certain
parasites, such aæ cattle grubs, which are the larvae
of the heel rly and the bomb fly~ have a known active
season when they attack animals. If such a parasite
is of primary importance, the compounds can be used
,
only during thht ~eason with assurance of year-round
control Or the parasite. Other parasites, such as
ticks, infest and bite animals essentially the year
round. Control of such parasites can stlll be accom-
plished ~ith relatively brief periods Or administratlon
.
X-3277B -54-
~06Q459
by administering the compound to ali t~e animals on a
farm or in an area ~or a short period of tlme, such a8
for a few weeks. All the parasites of a generation are
; thus killed, and the animals can be expected to remain
parasite-~ree for a considerable length Or time, for
example until reinfested by parasites arri~ing with
imported animals.
The compounds of formula II may be administered
by any of the usual oral and percutaneous routes. It
should be noted that many of the compounds are chemically
~ changed by passage through the rumen of a ruminant
r animal. Oral administration to ruminant animals is
therefore advisable only ir the compounds are protected
~rom the rumen en~ironment by a special formulation. Such
~ormulatlons wlll be dlscussed below
~he formulation and administration to animals
of biologically-effecti~e compounds is a ~ery old and
; developed art. Some explanation of the di~ferent
formulations and methods of administration will be given
to enable all to practice parasite control using these
compounds.
; -Percutaneous administration of formula
II compounds is carried out in the ways usual in
; the animal veterinary art. It is convenient to use a
. ~
~ater-soluble salt of the compound of formula II, so
that no elaborate formulation is required. On the
other hand, if a water-insoluble compound is desired,
I ~ ~ it is practical to dissolve the compound in a physio-
logically-acceptable solvent, such as the polyethylene
glycols. It is likewise practical to formulate
¦ X-3277B -55-
~ , , ,, . . , , . ,. , , ~,. .. . . . . . . .
106Q4S9
an injectable suspension o~ the compound as a fine
powder, ~uspended in a formulatlon of physiologically- -
acceptable nonsolvents~ surfactants, and suspending
agents.
The nonsol~ent can be, for example, a
vegetable oil such as peanut oil, corn oil or sesame
oil, a glycol such as a polyethylene glycol, or water, ~-`
depending on the compound chosen.
Suitable physiologically-acceptable ad~uvants ~;
are necessary to keep the compound o~ ~ormula II sus-
pended. The ad~uvants can be chosen from among the
emulsi~iers, such as salts Or dodecylbenzene sulrate
and toluenesul~onate, ethylene oxide adducts of
alkylphenol~ and oleate and laurate esters~ and from
the dlspersing agents such as salts o~ naphthalene-
sulronate, lignin sul~onate and fatty alcohol sul~ates.
Thickeners such as carboxymethyl cellulose~ polyvinyl-
pyrrolidone, gelatin and the alginates are also used as
adjuvants ~or ~n~ectable suspensions. Many classe~ of
surfactants, as well as~those which have been discussed
above, serve to suspend the compound. For example,
~ lecithin and the polyoxyethylene sorbitan esters are
I ~ useful sur~actants.
. ~
Percutaneous administration is conveniently
accomplished by subcutaneous, intramuscular, and even
ntravenous in~ection o~ the injectable formulation.
Conventional needle-type in~ection aevices as well as
needle-less air-blast in~ection devices are useful.
It is possible to delay or sustain the
,:1
permeation o~ the compound of formula II through the
x-3277B -56-
. ~
,
;
1~ .
~06Q459
animal'~ living tissues by proper formulation. For
example, a very insoluble compound may be used. In
that event, the slight solubility of the compound causes
sustained action because the body fluids of the animal
can dissolve only a small amount of the compound at any
one time.
Sustained action of the compound~ of formula
II can also be obtained by formulating the compound ln ~-
a matrix which will physically inhibit dissolution.
The formulated matrix is in~ected into the body where
it remains as a depot from which the compound slowly
dissolves. Matrix formulations, now well known in
the art, are formulated in waxy semisolids such as
~egetable WaXes and high molecular weight polyethylene
glycols
Even more effective su~tained action is ob-
tained by introducing into the animal an implant
containing one of the compound~ of formula II. Such
implants are now well known in veterinary art,
and are usually made of a silicone-containing rubber.
The compound is dispersed through a solid rubber implant
or is contained inside a hollow implant. Care must be
taken to choose a compound which is soluble in the
rubber from which the implant is made, ~ince it is dis-
persed by first dissolving in the rubber, and then
~:
leaching out of the rubber into the body fluids o~ the
treated animal.
The rate at which the compound is released
from an implant, and hence the length of time during
,
which the implant remains effective, is controlled with
X-~277B -57-
. .
.
~O~U459
good accuracy by the proper ad~ustment of the con-
centration of the compound in the implant, the external
area of the implant, and the formulation of the polymer
from which the implant is made.
Administration of the compounds by means of
an implant is a particularly preferred embodiment. Such
administration is highly economical and efficacious,
because a properly designed implant maintains a constant
concentration of the compound in the tiæsues of the host
animal. An implant can be designed to supply compound
for several months, and is easily inserted in the animal.
No further handling of the animal or concern over the
dosage is necessary after the insertion of the implant.
Oral administration of a compound of formula
II may be performed by mixing the compound in the
animal's feed or drinking water, or by administering
oral dosage ~orms such as drenches, tablets, or
capsules .
When a compound of formula II is to ~e ad- ;
ministered orally to a ruminant animal, it is necessary
to protect the compound from the deleterious effect of
; the rumen processes. The veterinary art
is now aware of effective methods for coating and en-
~ ~ .
capsulating drugs to protect them from the rumen. For
example, coating materials and methods are disclosed in
Grant et al., U.S. Patent No. 3,697,640. Grant
teaches a method of protecting substances from action
: ~ . ..
` of the rumen by coating the substances with a film of
cellulose propionate 3-morpholinobutyrate. Such a film
can be used to protect the compounas of formula II.
.
X-3277B -58_
~ .
iO604S9
Conveniently, tablets, or capsules containing a compound
of formula II are coated with the film in a coating pan ~ -
or a fluidized bed spray apparatus. Pellets of the
parasiticide may be made, coated with the film, and
filled into capsules. Alternatively, a solid mixture
of the compound and the film-forming agent may be made
and broken or ground into small particles, each of which
comprlses the compound enclosed in a matrix of the film-
forming agent. The particles may be filled into cspsules
for oral administration9 or made into an oral suspension.
The formulation of veterinary additives in
animal feed is an extremely well-known art. It i9 u8U
to formulate the compound first as a premix in which the
compound of formula II is dispersed in a liquid or
particulate ~olid carrier. The premix may con~eniently
contain from about 1 to 400 g. of compound per pound,
depending on the desired concentration in the feed. As
the art is aware, many compounds of formula II can be
hydrolyzed or degraded by constituents of animal feed.
Such compounds are routinely formulated in protectire
matrices such as gelatin before addition to the premix.
The premix i8 in turn formulated into feed by dis-
persing it in the feed mixture in a conventional mixer.
, ~ ~
The correct amount of compound, and hence of premix,
to mix in the feed is easily computed by taking into
acoount the weight of the animals, the approximate
a-ount each animal eats per day, and the concentration
of the compound in the premix.
Likewise, the amount o~ a compound to
administer in the drinking water of animals is computed
.
l X-3Z77B -59-
1~
., ~ : - . , . . ~.
. .......... : . . :
10~(~4S9
by taking into account the animal's weight and the amount
each animal drinks per day. It is most convenient to
use a water-soluble salt of a compound of formula II as
a drinking water treatment. If such a salt is not
desired, then a su~pendable formulation Or the desired
compound must be made. The formnlation may be a 8U8-
pension in the concentrated iorm, which suspension i6
mixed into the drinking water, or may be a dry preparation
which is mixed with and suspended in the drinking water.
In either event~ the compound must be in a finely-
powdered form, and the formulation follows the same
prlnciples discussed above for in~ectable suspensions.
The compounds can easily be formulated into
tablets and capsules according to the conventional
methods~ about which no teaching i8 required here.
Drench ~ormulations comprise the compound dissolved or
dispersed in an aqueous liquid mixture. Aga~n, it is
most convenient to make the drench by dissolving a water-
goluble salt of a compound Or formula II. It is almost
as convenient, however, and equally efficaciou~ to use
a dispersion of the compound made in the same way that
the drinking water formulations discussed above are
made.
The examples im~ediately below show the
effectiveness of the compounds of formula II ln con-
trolling a number of pzrasites which normally afrect
economic animals The compounds were tested again~t
screwworms, which are larvae of the black blowfly,
~against the stable fly, against mosquitos, and against
X-~277B -60-
,
106(~S9 ~:
the adult American dog tick. The blow~ly and stable ~ly
are in~ects; the dog tick is representQtive o~ the
acarina.
The stable ~ly is a common free-flying, blood~
sucklng parasite; the lone star tick is a typical blood-
sucking parasite which spends the nymphal and part Or
the adult periods of the li~e cycle attached to the host
animal, usually cattle. Blow~ly larvae, or screwworms,
hatch ~rom eggs laid near a wound of the host anlmal by
the free-flying insect. The lar~ae eat their way into
; the healthy ~lesh exposed by the wound and pass part o~
the life cycle therein, feeding on the host' B rleBh and
blood.
The ~table ~ly is parasitic on hor~es, mules,
cattle, hogs~ dog~ cats~ sheep~ goats~ rabbits~ and
human~. The lone star tick i~ primarily a cattle
parasite, but also attacks horses, mules, and sheep.
` ~ Blow~lg lar~ae attack any wounded animal, but are par-
ticularly harmful to cattle, hogs, horses, mules~ sheep~ ~ -
and goat~.
The following tests illustrate the efficacy
the compounds Or ~ormula II when they are ad~inls-
tered to cattle. In most instances, the tests reported
below were carried out on induced in~e~tations o~ para-
~ites.
: ,
: A calr was treated with 15 mg./kg. Or ~l
, (2,~2,3J3-tetrafluoropropionyl~-3'-nitro-5'-trifluoro-
methyl-g phenylenediamine a~ a single subcutaneous
:: '
injection. The compound was administered as a dis-
persion in lO percent polyvinylpyrrolidone.
X-3277~ -61-
,
,
lO~iQ459
Adult stable flies were housed in chambers
completely enclosed ln wire screen. Two or more chambers,
containing from 60 to 100 stable ~lies, were placed in
contact with the clipped back of the calf 24 hours a~ter
aaministration of the compound. The flies were left to
~eed on the calf ~or the time indlcated, a~ter which the
I chambers were obser~ed and the ~lies were le~t to ~eed
j for another time period. The mortality of the flies were
~ determined by countlng the number o~ lire and dead rlies
! lo after the exposure. Each set was run separately.
¦ The mortality results were as follows:
Hours Post- Stable Fly
¦ Set Treatment Mortalit
1 72 95
2 77 7Q
96 100
3 77 88
96 100
4 24 85
24 95
When the abo~e procedure was repeated using
mosquitos, rather than stable ~lies~ the result was:
: ~
Hours Post-
Set Treatment Mosauito MortalitY
1 96 100
~ '~'
hen the abo~e procedure wa~ repeated u~ing
~ ~ 25 mg./kg. in 10 percent poly~nylpyrrolidone, the
; ~ 30 results were:
1~ X-3277B -62_
;
-
.
1()604Sg :
Hours Post-
Set Pest ?reatment
1 mosquito 5 75
1 mosquito 24 100
2 mosquito 48 70
3 American dog
tick 168 86
N -(2,2,3,3-tetrafluoropropionyl)-3'-nitro-
5'-trifluoromethyl-o-phenylenediamine was tested at
10 mg./kg in sesame oil against stable rlies on a cal~.
The procedure was modified from the one described abo~e
`
in that the wire chambers ~ere.placed on the back of the
: calf 24 hours after àdministration of the compound. The - .~.
results are gi~en in the following table:
TAB L~3 X I
Time Alive ` Dead Percent ...
Day 1 :
6-hours 20 20 50
~ 24 hours 0 40 100 .- ::
:~ Day 2
6 hours 3 ~7 92
: 2024 hours 0 40 100
. Day 3
6 hours 16 24 60 ..
24 hour~ ; 4 36 90
; : : Day 4
6 hour.s 10 30 75
24 hou~s 0 40 100
Day 5
:: : 6 hours
:24 hours 0 40 100
Day 6
6 hours -- -- __
~ 24 hours 0 30 100
~: Dag 7
6 hours. 3 37 93
24 hours 6 34 85
: : '
: ~:
~ X-3277B _~3_
.c
i ::
,,,. . . : , ~ , ~ - :: :, . . .
10~0459
Time Alive Dead Percent
Day 8
6 hour8 35 5 12
24 hours 15 25 62
Day 9
6 hours 20 10 33
24 hours 0 40 100
Day 10
6 hours 40 0 0
24 hours 40 0 0 ~ -
Day 11
6 hours 40 0 0
24 hours 40 0 0
The tests reported immediately above demon-
strate the long-lasting control of insect and acarina
parasites which is obtained by the use of compounds Or
~ormula II. Administration o~ these compounds, even at
quite low rates, has been shown to kill such parasites
which ~eed on the treated animals even several days
after administration of the compound. It is also
notable that the control obtained was very complete,
in that all, or essentially all, of the parasite8 whlch
fed on the animal were killed.
The ~ollowing prpcedure reports representatlve
¦ results o~ a bio-assay test.
Larvae Or the black blowrly were used as assay
organisms in a bio-assay test system. The tests were
carried out by administering a compound Or thls in-
vention as a single subcutaneous injection to a calr.
Samples of blood were withdrawn from the calf on
successive days a~ter the administration of the compound~
and blowfly larvae were fed on the withdrawn whole
X-3277B -64_
1(~60~59
blood. The end point o~ the test was recorded as the
last day on which 90 percent or more of the blow~ly
lar~ae were killed. The results are gi~en in the
following table.
' '" ~'
~,
,
0
~:;; X-3277B -65-
.
~ ~O~Q459
a~
h
~ :'
o .~.
a1
..
~rl C
C~ ~I Q~
a) h s~
I~ Co ~1 CO ~o o o o CO o~ CO CO
O
h
Q~1 ~`
."
.. ., -
_
Y
O U~ U~ O U~ ~ O
OJ CU
O
0 C~
~ h
-I o ~ ,1 -
d a) ,I d s~ ~
'~ d
5~ o ~ o
~, ~d O ~I h h d
~rl h ~ -1~
a~o ~1 a~ o ~1
o 0 ~3 ~ ha~ h
o " a) ~ Oa O h
:
1,,
I ~ O ~ II
1~ I h ~: 0 U~ 0
h--` O
I O O ~1
a~ h r1 h ~I h h
~ ~ d ~ ~ .~1 ~
~1 I o ~ ~ ~ 0
. s:: ~ri h ~ O ~ al ~rl
~ .~ , h 1 ~3 ~
: O ~ O I I O - O ~J
P ~ - ol :1 ~ h
. ~ ' CJ P~ I O a)
o ~` o I ,1 ~ ~ ,1 ~ ,1
c~ h o h ~ ~1 h ~I h
~_ o
I
,1 ,1 .,1 ~ ~ ~ t) h
I
I, X- 3277B - 66-
. , .. . .. .. . . . . . - :. .. .. ..
1060gSg
An additional in vitro test for evaluating
the parasite control of adult stable flies by use of
the compounds o~ formula II is described hereinbelow.
Eighteen hour starved adult stable ~lies were placed ln
a petrie dish or fly cage and exposed to blood bait pads.
The blood in the pads was collected from treated calves
at desiænated time intervals, following treatment.
Mortality of the stable ~lies was determined at desig-
nated time intervals after exposure to the blood bait
pads. A percent mortality at these times was co~pared
to the normal mortality obtained in petrie dishes or
fly cages containing blood from non-treated calves
(control~. The compound used in this test was N -
(2~2,~,3-tetrafluoropropionyl~-3'-nitro-5'-trifluoro-
methyl-o-phenylenediamine. The results are given in the
~ollowing table,
.~ ~
.
:
X-3277B -67-
' '
.. ~ .. .. , , . ~ . .
1060459
.~
td . . .
o .. , -.
~: ,; .
N C~ O O O N ~ O a)
CO O O Oo~ CO O CO
C ~1 ~Ir-l ,1
h
~ ~.
~d : '
:
h o ~:1
a~ ~ o . ~-. .
~R ~ O
~o o m ~:
~ U~ ~ ~ C~ ~ ~ ~ ~ ~
u~ I ~ N N ^~ N N CU C~ CU
h ~ : . . -
:: '
O o ~
~ P~ . .,
H ~
H ~ i:
1 ~ h
:',,
~; O I . , .
E l ~1 ~
~1 ~q .. .
O O C~ o
C~ 14 t-- t-- C~ O CO
:~ ~ Iq
O h
.. ~0 ~o , ~,
m P::
.
.
: :
~- ~ I ~ U I ~ ~
~ o ~ ~ o ~ . .
bl O ~ ~ O ~ O
0 ~3 ~ h ~ ,~
~ o
.,~ h
~ ~ h
,- O U~ 1 0
:: ~ :
X- 3277B - 68_
.
106Q~S9
In the tests described above, the parasites
were exposed to the treated animal's blood indirectly,
instead of directly by feeding the parasites on the
animal. The control obtained, however, i8 obviously
as significant as if the parasites had sucked blood
directly from the animal. The value in protecting
animals from the very injurious parasite, the blowfly,
is clearly demonstrated by the tests, since several
days of parasite control were obtained from a single
administration of a compound Or formula II.
In addition to herbicidal, insecticidal~
and parasiticidal activity, compounds of the pre~ent
invention exhibit anthelmintic, and nemato¢idal activity.
The anthelmintic acti~ity is most pronounced
among compounds Or ~ormula II. The nematocidal acti~ity ~-
ls exhibited by compounds representati~e o~ formulae I,
II and III.
In respect to the anthelmintic activity, the
compounds Or formula II can be administered to warm-
blooded animals for the control of internal parasites,partlcularly parasites of the intestinal tract such as
Naemonchus contortus, Syphacia obvelata, and
NematosPiroides dubius. Administration is conveniently
by the oral route, and may take the form of inclusion
.: :
in a diet, or of separate administration o~ the subJect
' compound alone or formulated as a tablet or bolus ~or
administration. Typically, good results are obtained
.
at dosages of from 5 to 500 mg./kg. for single do~es~
and at dosages of from 0.001 to 0.05 percent in the diet.
X-3277B -69-
: :::
~0604S9
In representative procedures, Nl-trifluoroacetyl-3'-
nitro-5'-trifluoromethyl-o-phenylenediamine was incor-
porated in a modified mouse diet in a concentration of
0 01 percent. The modi~ied diet was fed to a group of
four mlce; an unmodified diet was ~ed to another group
of ~our mice to serve as a control. The mice of both
groups were infected with Nematospiroides dubius about
æeven hours after initiation of feeding. Feeding was
continued for eight days; on the ninth day, all mice
were necropsied and the upper intestines examined to
ascertain the presence, and if present numbers~ of
NematosPiroides dubius. In the group of mice on the
modified diet, no larvae were seen; in the control group,
an average of 28 larvae per mouse were seen. Like
re8ults are obtainéd with other of the compounds o~
formula II
The compounds of formulae I, II and III can
be used for the control of diseasescaused by fungal and
nematode organisms such as root-knot nematode, stem
nematode, fusarium root-rot, and Rhizoctonia. In
general, control is achieved at rates of from 1 to 40
pounds per acre. In standardized testing procedures,
~- the following compounds were found to give complete or
essentially complete control of root-knot nematode at
the designated application rate:
N -trifluoroaoetyl-3',4',5',6'-tetrachloro-
o-phenylenediamine (5 pounds per acre~ - -
~ N -trifluoroacetyl- ~ -naphthoyl-4'-tri-
- fluoromethyl-6'-nitro-o-phenylenediamine (20 pounds per
acre~
X-3277B -70-
~ .
'
iO604S9
N -tri~luoroacetyl-N2-(~4-dichlorobenzoyl)-
4'-trifluoromethyl-6'-nitro-o-phenylenediamine (20
pounds per acre).
The following examples illustrate the synthesis
of the compounds of formulae I, II and III and will enable
those skilled in the art to practice the present in-
vention.
Example l
3,4,5,6-Tetrachloro-o-phenylenediamine
(2.0 grams~ was dissolved in 50 milliliters of benzene
and o.8 milliliter of triethylamine and the solution
treated with trifluoroacetic anhydride (1.84 grams~.
The resulting reaction ~ixture was then heated to reflux,
refluxed ~or 16 hours, condensed by evaporation to 20
milliliter~, and the desired N -trifluoroacetyl-3',4',
5',6'-tetrachloro-o-phenylenediamine product separated
by filtration and recrystallized from chloro~orm, m.p.,
245-47C.
Example 2
Finely ground 3-trifluoromethyl-5-nitro-o-
phenylenediamine (2.2 grams), triethylamine (l.0 ml.), -
and chloroform (10 milliliters) were mixed and stirred -
~hile trifluoroacetic anhydride (2-3 milliliters in
chloroform [20 milliliters]~ was added. The addition
was carried out portionwise over a period of 20 minute~
and at room temperature. The resulting reaction mixture
was filtered to separate the desired Nl-trifluoroacetyl-
3'-trifluoromethyl-5'-nitro-o-phenylenediamine product
which was recrystallized from benzene, m.p., 201-02C.
..
X-3277B -71-
~0604S9
AnalYsis~ Calc. for CgH5F6N303
(percent~: C~ 34.o8; H, l.sR; N, 13.24.
Found: C, 34.24; H, 1.60; N, 13.24.
Exam~le 3
3-Nitro-5-trifluoromethyl-o-phenylenediamine
~! (5 0 grams~ was mixed with 15 milliliters of pyridine
and the mixture cooled to 0C. Chlorodifluoroacetyl ~ -
chloride (3 milliliters) was then added with stirring
over a period of 20 minutes. After standing at 20C.
for about 1.5 hours, the reaction mixture was mixed
with 150 grams of ice and 20 milliliters of hydro-
chloric acid, which resulted in the precipitation of the
de~ired Nl-chlorodifluoroacetyl-3'-nitro-5'-trifluoro-
methyl-o-phenylenediamlne product. It wa~ separated
by ~iltratlon and recrystallized from benzene, m.p.,
186-88C.
Exam~le 4
~ -Benzoyl-6-nitro-4-trifluoromethyl-o-
phenylenediamine (3.2 grams) and excess trifluoroacetic
anhydride were mixed and allowed to stand o~ernight.
Exce~s trifluoroacetic anhydride and the corresponding
by-product acid were evaporated under ~acuum to separate
the decired N -trifluoroacetyl- ~-benzoyl-6'-nitro-4'-
trifluoromethyl-o-phenylenediamine product, which,
-after recrystallization from benzene, melted at 193-
95C.
.
Exam~le 5
Other compound~ representative of the pre~ent
invention are readily prepared in the procedure~ of the
X-3277B -72-
,. . . ... , ~ ~ - - : . . . . .
iO604S9
foregoing teachings and examples, using analogous
starting materials. Such compounds include the
following:
Nl-Trifluoroacetyl-3'-nitro-5'-trifluoro-
methyl-o-phenylenediamine, m.p., 194-95C., prepared
by rsacting trifluoroacetic anhydride with 3-nitro-5-
trifluoromethyl-o-phenylenediamine.
Nl-Propionyl-N2-(2~2-difluoro-3-iodopropionyl)-
5'-(sec-butylsulfonyl~-o-phenylenediamine, prepared by
reacting 2,2-difluoro-3-iodopropionyl chloride with N -
propionyl-5-(sec-butylsulfonyl)-o-phenylenediamine.
N ,N -Bis(trifluoroacetyl)-5'-(methylsulfonyl)-
o-phenylenediamine, m.p , 179-81C., prepared by reacting
trlfluoroacetic anhydride with 5-(methylsulronyl)-o-
phenylenediamine.
N -Trlfluoroacetyl-N -~-toluoyl-5',6'-
dichloro-o-phenylenediamine, prepared by reacting tri-
fluoroacetyl chloride with N2-~-toluoyl-5,6-dichloro-o-
phenylenediamine.
N -Trifluoroacetyl-N -acetyl-4'-(methyl-
sulfonyl~-o-phenylenediamine, m.p., 200-01C., prepared
by reacting trifluoroacetic anhydride with N2-acetyl-4-
(methylsulfonylj-o-phenylenediamine.
Nl-Difluorochloroacetyl-N -hexanoyl-5'-
(n-propylsulfonyl~-o-phenylenediamine, prepared by
reacting difluorochloroacetic anhydride with N -hexanoyl-
5~(n-propylsulf~nyl~-o-phenylenediamine.
-N -Trifluoroacetyl-3'-nitro-5'-chloro-o-
phenylenediamine, m.p., 184-86C., prepared by reacting
30~ trifluoroacetic anhydride with 3-nitro-5-chloro-o-
X-3277B _73_
,~
' ' '
- ~06045;9
phenylenediamine. `
Nl-(3-Bromopropionyl)-N2-trifluoroacetyl-S'-
(ethylsulfonyl)-o-phenylenediamine, prepared by reacting
trifluoroacetic anhydride with Nl-(3-bromopropionyl)-5-
(el:hylsulfonyl)-o-phenylenediamine.
Nl-(2,2-Difluoro-3-bromopropionyl)-N2-
(2 chloro-4-tert-butylbenzoyl)-3'-nitro-5'-trifluoro-
methyl-o-phenylenediamine, prepared by reacting 2,2-
difluoro-3-bromopropionyl chloride with N2 _ (2-chloro-4-
tert-butylbenzoyl)-3-nitro-5-trifluoromethyl-o-phenylene-
diamine.
Nl-Trifluoroacetyl-N2-(methoxycarbonyl)-5',6'-
difluoro-o-phenylenediamine, prepared by reacting tri-
fluoroacetic anhydride with N2 _ (methoxycarbonyl)-5,6-
difluoro-o-phenylenediamine.
Nl -Difluorochloroacetyl-N2-~phenoxycarbonyl)-
3'-nitro-5'-difluoromethyl-o-phenylenediamine, prepared
by reacting difluorochloroacetic anhydride with N2 _
(phenoxycarbonyl)-3-nitro-g-difluoromethyl-o-phenylene-
diamine.
Nl-Difluoroacetyl-N2-(3,4-dichlorobenzoyl)-
` 5'-chloro-o-phenylenediamine, prépared by reacting di-
,~ .
fluoroacetic anhydride with N~ - (3,4-dichlorobenzoyl)-
5-chloro-o-phenylenediamine.
N - Pentafluoropropionyl-N -(5-bromo-m-
toluoyl)-3',4',5',6'-tetrachloro-o-phenylenediamine,
prepared by reacting pentafluoropropionic anhydride with
~ q
N~ - (5-bromo-_-toluoyl)-3,4,5,6-tetrachloro-o-phenylene- s
diamine.
.:
~30
~ .
; -74-
, :,
106045~
Nl-Heptafluorobutyryl-N2-(sec-butoxycarbonyl)-
4'-bromo-o-phenylenediamine, prepared by reacting hepta-
~ fluorobutyric anhydride with N2-(sec-butoxycarbonyl)-4-
bromo-o-phenylenediamine.
Nl-(2,2-Difluoropropionyl)-N2-t3-nitro-5-
isopropoxybenzoyl)-5',6'-dichloro-o-phenylenediamine,
prepared by reacting 2,2-difluoropropionyl bromide with
N2-(3-nitro-5-isopropoxybenzoyl)-5,6-dichloro-o-
phenylenediamine.
Nl-Trifluoroacetyl-N2-naphthoyl-6'-nitro-4'-
trifluoromethyl-o-phenylenediamine, m.p., 200-04C., -
prepared by reacting trifluoroacetic anhydride with N2-
naphthoyl-6-nitro-4-trifluoromethyl-o-phenylenediamine.
Nl-Iodoacetyl-N2-trifluoroacetyl-5'-
(methylsulfonyl)-o-phenylenediamine, prepared by reacting
trifluoroacetic anhydride with Nl-iodoacetyl-5-(methyl-
sulfonyl)-o-phenylenediamine.
Example 6
Other compounds of formulae I, II and III
prepared by the procedures of the previous examples and
discussion are
N~-Trifluoroacetyl-N2-(p-_-butoxybenzoyl)-
4'-trifluoromethyl-6'-nitro-o-phenylenediamine, m.p.,
172-74C.
N -Trifluoroacetyl-N2-(~-nitrobenzoyl)-4'-
trifluoromethyl-6'-nitro-o-phenylenediamine, m.p.,
210-12C.
Nl-Trifluoroacetyl-N2-(2,4-dichloro-6-methoxy-
~benzoyl)-6'-nitro-o-phenylenediamine, m.p., 200-01C.
~.
-75-
. .
, .. , ., ~ ~ .. . .- .. .. ... . . .
- ~O~Q459
N -Heptafluorobutyryl-3'-nitro-5'-tri-
fluoromethyl-o-phenylenediamine, m.p., 118-20C.
Nl-Pentafluoropropionyl-3'-nitro-5'-tri-
fluoromethyl-o-phenylenediamine, m.p., 161-63C.
Nl-Trifluoroacetyl-N2-methoxycarbonyl-4'-
trifluoromethyl-6'-nitro-o-phenylenediamine, m.p.,
129-30C.
Nl-Pentadecafluorooctanoyl-3'-nitro-5'-
trifluoromethyl-o-phenylenediamine, m.p., 111-13C.
Nl-Trifluoroacetyl-N2-benzoyl-3'-trifluoro- - '
methyl-5'-nitro-o-phenylenediamine.
Nl-Trifluoroacetyl-N2-naphthoyl-4'-trifluoro-
methyl-6'-nitro-_-phenylenediamine.
N -Trifluoroacetyl-N2-trichloroacetyl-3'-
nitro-5'-(methylsulfonyl)-o-phenylenediamine.
Nl-Pentadecafluorooctanoyl-N2-acetyl-4'-
(methylsulfonyl)-o-phenylenediamine.
N1,N2-Bis(heptafluorobutyryl)-4'-(methyl-
8ulfonyl)-o-phenylenediamine.
Nl-Trifluoroacetyl-N2-acryloyl-4'-(methyl-
sulfonyl)-o-phenylenediamine.
Nl-Trifluoroacetyl-N2-propioloyl-4'-(methyl-
sulfonyl)-o-phenylenediamine.
Nl-Trifluoroacetyl-N2-benzoyl-4'-(ethyl-
sulfonyl)-6'-nitro-o-phenylenediamine.
~; Nl-Pentaf1uoropropionyl-N2-naphthoyl-4'-
~; (methylsulfonyI)-o-phenylenediamine.
Nl-Difluoroacetyl-N2-metho~ycarbonyl-4 ' -
:
~ (methylsulfonyl)-o-phenylenediamine.
: :~
.
-76-
.
10~04S9
Nl-Heptafluorobutyryl-N2-p-toluoyl-4'-
(methylsulfonyl)-6'-nitro-o-phenylenediamine.
- Nl-Trifluoroacetyl-N2-benzoyl-4',5'-dichloro-
-E~hen~lenediamine.
Nl-Trifluoroacetyl-N2-naphthoyl-4'-nitro-o-
phenylenediamine.
Nl-Trifluoroacetyl-N2-furoyl-5'-(methyl-
sulfonyl)-o-phenylenediamine, m.p., 185-87C.
Nl-Difluoroacetyl-N2-furoyl-3'-nitro-5'-
trifluoromethyl-o-phenylenediamine.
Nl-Chlorodifluoroacetyl-N2-furoyl-4',5'-
dichloro-o-phenylenediamine.
Nl-(2,2,3,3-Tetrafluoropropionyl)-N2-methoxy-
carbonyl -6'-nitro-4'-trifluoromethyl-o-phenylenediamine,
m.p., 129-30C.
~ 1-(2,2,3,3-Tetrafluoropropionyl)-3'-nitro-
5'-trifluoromethyl-o-phenylenediamine.
Nl-(2,2,3,3-Tetrafluoropropionyl)-3'-nitro-
5'-trifluoromethyl-o-phenylenediamine, m.p., 144-45C.,
prepared by reacting 2,2,3,3-tetrafluoropropionyl
bromide with 3-nitro-5-trifluoromethyl-_-phenylene-
diamine.
Nl-Pentafluoropropionyl-3'-nitro-5'-
trifluoromethyl-o-phenylenediamine, m.p., 161-53C.,
prepared by reactlng pentafluoropropionyl bromide with
3-nitro-5-trifluoromethyl-o-phenylenediamine.
-77-
