Note: Descriptions are shown in the official language in which they were submitted.
1t)~7~S~
This invention relates to the formula I pyrazolium compounds
having the structurc below and to a process for their preparation.
1 R2 ,~
_ _ m
wherein Rl and R2 each represents alkyl Cl-C4; R3 represents a member selected
from the group consisting of cycloalkyl C3-C7, cycloalkenyl C3-C7, ~ :
-(CH2)n ~ , and alkyl C2-Cll; R4 represents a member selected from ``-
the group conslsting of cycloalkylmethyl C3-C7, cycloalkyl C3-C7, methyl- ~ ~
substituted cycloalkyl C3-C7, cycloalkenyl C3-C7, methyl-substituted cyclo- `
alkenyl C3-C7, alkyl C2-Cll and -CH2 ~ ; Y, Y~, Z and Z' each repre- ~
Z ' Y ' `' ~ ~ '
sents members selected from the group consisting of hydrogen, halogen, nitro,
methylthio, methylsulfonyl, cyano, carboxyl, carboalkoxy Cl-C4, alkyl Cl-C4,
haloalkyl Cl-C4 containing 1 to 4 halog~n groups and alkoxy Cl-C4; X repre-
sents an anion with a charge of from 1 to 3; n is O or 1 and m is an integer ;~.
from 1 to 3. The invention also relates to a method for controlling undesir~
able plant species with the formula I compounds.
The diketone precursors used in preparing the formula ~I) pyra-
zolium salts having the structure:
',', :.,
:.~
_ 1 -
: . ~ : - - - - ,- ; . . . . ;
.: . : . . : . , . . - ,
- . - - : . -~ : .
~ `
~379S~ :
R.. ,~, :R3 ~ ~ :
~I) ~ X ~ ~:
N N
Rl R
_ _ m
where Rl, R2, R3, R4, m and X are as described above, are pre~
pared by reacting a methyl ketone (II) with an alkyl carboxylic
10 acid ester (III), preferably the methyl or ethyl ester, in the ~;
presence of an alkali metal hydride, preferably sodium hydride,
and an aprotic organic solvent, such as dimethyl sulfoxide
: . `?
(DMS0), dimethyl formamide (DMF), xylene, toluene, benzene or
the like. The reaction is preferably carried out at a tempera~
ture between 0C. and 40C. and most preferably between 0C.
and 25C. The reaction yields the ~-diketone corresponding to `
the reactants employed. The methyl ketone and carboxylic acid
ester react in equimolar amounts; however, it is generally de-
sirable to employ a s~iight excess, i.e., up to about 10% excess,
of the carboxylic acid ester in the reaction mixture. The re~
action can be illustrated as follows~
O o `~
R3COCH3 + C2H50C-R4 NaH ~ R3-C-CH2-C-R4 3 ,'
(II) (III) (IV)
wherein R3 and R4 are as defined above.
The process of the present invention for the prepar- `~
ation of the formula (I) compounds involves first condensing
the formula (:~) diketone with either hydrazine or a C--C~ al-
kyl hydrazine to form the corresponding 3,5-disubstituted py-
razole which is alkylated to form the desired formula (I) py-
razolium salt. These reactions are graphically illustrated
below.
- 2 - ~-
~,.. .
~379S~
O O R4 R3
R3-C-CH2-C-R4 RNHNH2 3 ~ / alk~lation
(IV) ll
N -
R
1~
N - N
Rl R2 m
wherein R is hydrogen or alkyl Cl-C4 and Rl, R2, R3, R4, m
and X are as defined above. The symbol ~~~~ indicates al-
ternative points of attachment of the R substituent.
The term "halogen", as herein used, i~ intended
to include fluorine, chlorine, iodine or bromine: however,
fluorine, chlorine and bromine are preferred.
Illustrative of the anions whioh are &uitable
for use in the present invention are halides, such as chloride,
bromide and iodide; sulfate; hydrogen sulfate; methyl sulate;
benzene sulfonate; perchlorate; Cl-C4 alkoxy benzene~sul-
fonate; C1-C4 alkyl benzene sulfonate, preferably ~-toluane
sulfonate; phosphate, Cl-C4 alkane sulfonate
oq R6 ~8
-O-C-C-R5 and -O-C-CH-O - ~ Cl, where R5 is halogen,
7 Rg/~
methyl, halomethyl or dihalomethyl; R6 and R7 are hàlogen;
R8 is hydrogen or methyl; and Rg is chlorine or methyl.
'.
~ . ~ 3 ~
.
~L0~7~
The diketone and the hydrazlne react ln equimolar
amounts. However, a slight excess, up to about 10% of either
reactant, may be advantageously used. This reaction is usual-
ly carried out in the presence of a solvent, either protic or
aprotic, at a temperature between about 70C. and 150~. and
preferably between 80C. and 120C. Preferred solvents for
these reactions are protic solvents, such as the lower alcohols
including methanol, ethanol, n-propanol, isopropanol, n-butanol
and isobutanol. Aprotic solvents which are suitable for use in
these reactions include xylene, toluene, benzene, dimethylsul-
foxide, dimethylformamide, and pyridine. The introduction of
an acid catalyst~ such as p-toluene sulfonic acid~ increases
the rate of the condensation-cyclization reaction and can be
advantageously used if the reaction is proceeding slowly.
Advantageously, when hydrazine is used in the init-
ial ~ondensation of the diketone, alkylation of the resulting
pyrazole is accomplished by means of a known alkylating agent,
preferably in the presence of an acid acceptor, such as an al-
kali metal hydroxide, an alkali metal alkoxide or a tertiary
20 organic amine. Preferred acid acceptors encompass sodium or ;
potassium hydroxide, sodium or potassium methoxide, ethoxide,
propoxide or t-butoxide, trimethylamine, triethylamine and py-
ridine.
Alkylations of the pyrazole are preferably carried
ou~ in the presence of a solvent at a temperature between 50C.
and 200C. and, preferably~ between 90C. and 120C. Preferred
solvents include aromatic hydrocarbons such as toluene, xylene
:; ~: ..
and chlorobenzene; ketones having 4 to 7 carbon atoms such as
the methylisobutylketone (MIBK) and methylbutylketone (MBK);
~0 C2-C5 alcohols; dipolar aprotic solvents such as dimethyl sul-
foxide ~DMS0), dimethylformamide (DMF), acetonitrile~ nitro-
benzene and N,N-dimethylacetam~de; and cyclic ethers, such as
dioxane and tetrahydrofuran.
~: , -
.
~(~379.5~3
Exemplary of the alkylating agents are: alkyl hal-
ides, dialkyl sulfates, alkyl phosphates, alkyl hydrogen sul-
fates, and alkyl toluene sulfonates; with these alkylating
agents, the alkyl groups e~ch have 1 ~o 4 carbon atoms. Among
the preferred alkylating reagents are the alkyl halides) such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl and
tert-butyl chlorides and bromides; dialk~l sulfates, alkyl hy-
drogen sulfates, and toluene sulfonates.
While the 3,5-disubstituted pyrazoles combine with
equimolar amounts of the alkylating agent, it is a good prac
tice to employ an excess of alkylating reagent. Mole ratios
of alkylating reagent to pyrazole within the range of from 1:1 '
- to 1.5:1 are preferred. Obviously twice the molar quantity of
- alkylating agent will be required where hydrazine is employed. ~
15In these alkylation reactions it is frequently found ~ -
that on cooling of the reaction mixture the solid or oily pyra-
zolium salt separates and is purified by separation from the -
organic layer. However, in some instances, particularly those
wherein R3 and R5 are highly lipophilic (e.g.) the 3,5-dicyclo~
hexyl, 3-cyclohexyl-5-phenyl and 3-dodecyl-5-phenyl compounds),
separation of the pyrazolium salt from the organic phase cannot
be readily accomplished. In such cases, the product can be ob-
tained by evaporation of the solvent, and dissolving the resi-
due in chloroform, water washing of the chloroform layer and
;25 evaporation of the chloroform to obtain the pyrazolium salt as
the residue.
Utilizing toluene sulfonates or methylsul~ates as
alkylating agents, impure or hygroscopic materials are fre-
. .: . ,.
quently obtained due to anion contaminations (such as HSO~ or `
30 S04 ). In such ~nstances, the mixed anion is purified by pas- ~`
sing an aqueous solution of this mixture through an anion ex- ` ~- -
change column. Alternatively, the aqueous solution of mixed
anions may be converted to an iodide using aqueous saturated ; ~-
.
3795t~
potassium iodide or sodium iodlde solution. The latter treat-
ment yields the relatively water-lnsoluble iodide. Perchlor-
ates are prepared by addition of dilute aqueous perchloric acid
to an-aqueous pyrazolium salt solution to give the water-lnsol-
uble perchlorate. Additionally pure pyrazolium salts, e.g.,
CH3S04 , HS04-, S04 or Cl may be converted by the above men-
tioned procedures of anion exchange chromatography to a new py-
razolium salt, and to iodides and perchlorates as defined above.
The pyrazolium halides are prepared as hereinabove described,
except that the reaction is conducted in a sealed vessel or
glass-lined bomb maintained at a temperature of about 100C.
A further aspect of the present invention involves
the application of a herbicidally effective amount of a com-
pound of formula ~I) to the foliage of undesirable plants. `
'~hey are employed at rates between about 0.25 pound per acreand 10.0 pounds per acre and, preferably, used at rates be~
tween 0.50 and 5.0 pounds per acre. Surprisingly, these com-
pounds also have utility as mildewcidal agents, when applied
to the foliage of plants at rates between about 0.25 and 10.0
pounds per acre.
. Formula (I) pyrazolium salts where R3 is phenyl, R4
is alkyl C2-Cl1 (preferably C5-Cll) and Rl, R2, m and X are as ~
defined above, exhibit excellent selective postemergence broad- -- ;
leaf control in the presence of small grains, such as barley,
wheat and rice. This is especially surprising~ since the known
lower homologue, i.e., where R4 is methyl, is ineffective as a
herbicidal agent at all rates tested. Surprisingly, these -
compounds also possess preemergence herbicidal
activity. `~
As will be noted below, the formula (I) pyrazolium ~
salts which are most unusual in their herbicidal effectiveness ~ -
are those in which R4 represents a cycloalkyl C3-C7 group and ~ ;
Rl, R2, R3, m and X are as defined above. Preferred compounds
,
~ 37~
are those in which R3 is cycloalkyl C3-C7 or -~C~l2) ~ ~ ;
R4 is cycloalkyl C3-C7; Rl and R2 are methyl; and X, Y, Z and n and m are as ;-defined above. These compounds are highly effective herbicidal agents. They
are particularly effective when applied to the foliage of undesirable plants
and are active against both broadleaf weeds and undesirable grasses. More-
over, they can be used for selectively con~rolling wild oats~ broadleaf weeds ``
and undesirable grasses especially crab grass, in the presence of small.
grains such as barley, wheat and rice. Still more surprising is the fact that
said compounds also exhibit preemergence herbicidal activity.
Other preferred compounds are those in which R3 is phenyl and
R4 is alkyl C2-Cll, especially n-pentyl or undecyl; R3 and R4 are each cyclo-
alkyl C3-C7; R3 is phenyl and R4 is cycloalkyl C3-C7; and R3 is phenyl and
R4 is benzyl.
Advantageously, many of the formula ~I) pyrazolium salts demon- `
strate a high degree of water solubility and lend themselves to the prepara- ;
tion of aqueous concentrates. Among the preferred salts are the methyl sul-
fates, hydrogen sulfates, sulfates, chlorides and bromides. In practice, the
aqueous concentrates may be applied directly as a liquid spray to the foliage
of undesirable broadleaf weeds and grassy plants. Alternatively, they may
be further diluted with water and applied as dilute aqueous sprays to these
undesirable plants. ;
The water-miscible concentrates are prepared by dissolving from
15% to 95% of the compound in 85% to 5% of a water-miscible solvent, such as
water itself or another polar water-miscible solvent, such as 2-methoxy ethanol, methanol, propylene glycol, diethylene glycol, diethylene glycol monoethyl
ether, formamide, and dimethylformamide. Application of the material is made ~-
by adding a predetermined quantity of the water-miscible concentrate to a ~;
spray tank and applying the mixture as such or in combination with a suitable
diluent, such as a further quantity of water or one of the above polar solvents.The performance of the product in all of the above
-- 7 --
~.~ ,' .i . .- - . .. - . ~
. . . ~ . .
~ ~7~3158
formulations, whlch are applied as liquld sprays, ls unexpec-
tedly improved by adding a surfactant or blend of surfactants.
Conventional anionic, cationic and anionic-nonionic surfactants
may be employed
Illustrative nonionic sur~actants are: alkyl poly- ;
oxyethylene ethers, polyoxyethylene (20) sorbitan monolaurate,
pol~oxyethylene (20) sorbitan monooleate, alkylarylpolyglycol
ethers, alkyl phenol ethoxylates, trimethyl nonyl polyethylene
glycol ethers, alkyl phenol ethylene oxide condensatesg octyl
phenoxy polyethoxy ethanols, nonylphenyl polyethylene glycol
ethers, condensates of polyoxy ethylenes, polyoxypropylenes,
aliphatic polyethers, aliphatic polyesters, alkylaryl polyoxy~
ethylene glycols, and the like.
Exemplary anionic surfactants include sodium dodecyl-
- 15 ~en~ene sulfonate and the dioctyl ester of sodium sulfosuccinic
acid.
Suitable cationic surfactants include dicoco dimeth-
ylammonium chloride, stearamidopropyl dimethyl betahydroxy- `
. ethylammonium nitrate and the like.
These surfactants are preferably added to the spray
tank at the rate of 0.1~ to 5% by volume to provide good wet~
ting of the spray solution on plant foliage.
Herbicidal concentrates containing surfactants are
preferably formulated as aqueous sprays containing approximate~
ly 30~ by weight of the appropriate pyrazolium salt, from about
25% to 50% by weight of water and the remainder of said formu- ~-
lation (25~ - 45% weight) of a selected surfactantO Surfac- -
tants which are especially useful in preparing suitable sur-
factant containing concentrates include an octylphenol ethy-
lene oxide condensate, an ethanolic solution of an alkyl phen-
ol ethoxylate, a polyglycolic ether condensate produced from
ethylene oxlde and an alkyl phenol, and an alkyl aryl polygly- -
colic ether.
~'", "
- 8 - ~
~03795~3
Other ~ormulations which may be used to advantage
wlth the compounds of this invention include dusts, dust con-
centrates and wettable powders.
Dusts are generally prepared by grinding together
about 1% to 25% by weight of the active agent with from about
99% to 75~ by weight of a solid diluent such as kaolin, atta-
pulgite, talc, pumice, diatomaceous earth, ~ullers earth, wood ` !~
`~ ~ . . ; ` .
~lour, or the like.
Dust concentrates are prepared in similar fashion ex~
cepting that about 25~ to 95% by weight of the active agent is
ground with about 75% to 5% by weight of the diluent.
Wettable powders are prepared in the same manner as
the dust concentrates excepting that about 1% to 5% by weight
of a dispersing agent such as the calcium salt of a polymerized
~lkvl aryl sulfonic acid, sodium lignosulfonate, or sodium salt
of condensed naphthalene sulfonic acid is blended with the mix- ;
ture and about 1% to 5~ of a surfactant, such as polyoxyethyla- ~ ~;
ted vegetable oil, alkyl phenoxy polyoxyethylene ethanol, so~
dium alkyl naphthalene sulfonate is also blended with the for-
20 mulations. `~
In practice, the wettable powder is dispersed in wa- ~ `
ter and applied as a liquid spray to the foliage of undesirable
plants. Application rates should be sufficient to provlde
about 0.25 to 10 pounds per acre of the pyrazolium salt and,
although 0.5 to 500 pounds per acre of said salt is generally ; `~-
satisfactory to control undesirable broadleaf weeds and undes-
irable grass plants, it should be recognized that rates exceed~
ing 10 and as high as 20 pounds per acre can be used. These
~ ~.. ~... .
higher rates would, Or course, be used in areas such as rail- `~-
~0 road sidings, beneath power lines and along hedge rows border~
- ing property lines and fields.
In order to facilitate a further understanding of
the invention, the following examples are presented primarily `
_ g _ ''
.. , .. ~,,
, . - .. .. .. - - - i
~0379S~ ;
for the pur~ose of illustratin~ certain more speclfic details
thereof and also to illustrate preparation of starting materi-
als useful therefor. Unless otherwise noted, all parts and
percentages are by weight.
EXample 1
Preparation o~ Dicyclohexyl-1l3-Pro~anedione
~ .
50dium hydride (39.5 g. of 54%, o.889 mole) is cooled
- wlth an icebath to 18C. in a suitable flask fitted with stir-
rer, condenser, drying tube, dropping funnel and thermometer.
Dimethyl sulfoxide (700 ml.), dried over 4A molecular sieves,
is slowly added. After addition is complete, the reaction mix-
ture is stirred for 0.5 hour at room temperature. The icebath
is replaced and a mixture of cyclohexane-carboxylic acid, eth~
~1 ester (138.8 g.J o.889 mole)~ and cyclohexyl methyl ketone
15 ~101.9 g., 0.80 mole) are added dropwise. No exotherm is ob-
served. The reaction mixture becomes lighter in color and
some bubbles are observed. After the addition has been com~
pleted, the icebath is removed and the reaction mixture is
stirred overnight at room temperature. The thick, deep bu~f
colored reaction mixture is poured over ice (8 liters~ contain~
ing phosphoric acid (50 ml.) and extracted with ether. The
ether is washed with water, dried and vacuum stripped to yield
a golden yellow oil (204 g.) which smells strongly of the es-
ter. The product can be purified by reaction with copper com- ``~
plexes according to conventional procedures if desired. When
! pure it is in the form of white crystals having a melting point
of 50C. - 52C.
Anal. Calc'd for Cl5H2402: C, 76.22; H, 10.24.
Found: C, 76.20; H, 10.03.
Other ~-diketones can be prepared from esters and ke-
tones containing R3 and R4 as previously defined Thus, l-cy-
clopropyl-3-phenyl-1,3-propanedione has been reported to be `
prepared as a solid, mp 35C. - 37C., from ethyl benzoate and
- 10-
,
~37~S~
cyclopropyl methylketone in the presence of sodium amide. Al-
ternatively, it has been found thiat the same compound, mp 38C -
~40C. could be ~re~ared from lethyl cyclopropane-carboxylate,
acetophenone, and sodium hydrlde. Furthermore, a series Or 1-
alkyl-3-phenyl lJ3-propanediones have been prepared from car-
boxylic acid ethyl esters and acetophenone in the presence of
sodium amide. Illustrative examples are tabulated employing
the following equation~
O O
R3COCH3 + C2H50CR4 N H ~ R3CCH2CR4
(II) (III) (IV) ~i
where R3 and R4 are set forth in the Table I below. ~ ;
~
,:. .
., ~
,,'' ~'" ' .,
-
','. .'
, ,; '
;
~379~
~1 ~ ~r_i~
~ ~ ~0~ 30
c
' :~ ~
~ ~0379S~
Other ~ropanedlones which can be prepared by the
above procedure using the appropriate carboxyllc acid esters
and substituted methyl ketones are:
1,3-Dicyclohexenyl-1,3-propanedlione
5 1,3-Dicyclo~entenyl-1,3-propanedione ;
1,3-Dicyclohexyl-1,3-propanedione
: l-Phenyl-3-n-pentyl-1,3-propanedione ;
l-P~enyl-3-cycloheptane-1,3-propanedione
l-Phenyl-3-undecyl-1,3-propanedione ~ ;~
1,3-Dibenzyl-1,3-propanedione
- l-Benzyl-3-cyclohexyl-1,3-propanedione . `
l-(l-Methylcyclohexyl)-3-phenyl-1,3-propanedione
1-(2-Methylcyclohexyl)-3-phenyl-1,3-propanedione
1,~-Di-_-butyl-1,3-propanedione . .
1-Cyclohexyl-3-(m-tolyl)-1,3-propanedione
l-Cyclohexyl-3-(o-fluorophenyl)-1,3-propanedione
l-(p-Chloro~henyl)-3-cyclopentyl-1,3-propanedione :
l-(p-Bromophenyl)-3-cyclohexyl-1,3-propanedione ~ ~`
l-Benzyl-3-(p-methylthiobenzyl)-1,3-propanedione
20 1-Cyclohexyl-3-(p-cyanophenyl)-1,3-propanedione .
, . . ~ . .
l-Cyclohexyl-3-(m-trifluoromethylphenyl)-1,3-propanedione
l-p-Anisyl-3-n-hexyl-1,3-propanedione
l-Cyclohexylmethyl-3-phenyl-1,3-propanedione
1,3-Dicyclopropylmethyl-1,3-propanedione
1,3-Dicyclopropyl-1,3-propanedione
l-Cyclohexyl-3-ethyl-1,3-propanedione `~
l-Cyclopentyl-3-phenyl-1,3-propanedione
1,3-Dicyclohexylmethyl-1,3-propanedione
:. ~
l-Cyclohexyl-3-(~-methylsulfonylphenyl)-1,3-propanedione
30 1-(2-Carboxyphenyl)-3-cyclohexyl-1~3-propanedlone, as the `~
disodium salt
1-(2-Carboxyphenyl)-3-cyclopentyl-1,3-propanedione, as the :~
d~sodium salt
- 1
-
037 9 ~ ~
l-Benzyl-3-(2-carboxy~henyl)-lJ3-propanedione~ as the disodium -
salt
Exam~le 2
Preparation of ~-Cyclopropyl-l-methyl-5-phenylpyrazole and 5-
Cyclopro~yl-l-meth~ -phenyl~yrazole `~
l-Cyclopropyl-3-phenyl-1,3-propanedione (37.6 g. J
0.2 mole) and 2-propanol t250 ml.) are heated to reflux. Meth-
yl hydrazine (10.2 g., 0.22 mole) is then added dropwise, and ;
the solution refluxed until the reaction is complete (2.5
hours). The solution is then filtered and vacuum stripped to
give a yellow oil (39.2 g., 99~). Examination o~ the product ;~
on a silica gel thin layer chromatography plate developing with
chloroform and iodine shows the presence of an lmpurity. The
product is chromatographed on silica gel with chloroform to ;~
~iV2 a white, cloudy oil. The isomers may be used as a mix-
ture or isolated by conventional chemical separation techniques ~ `
such as by fractional crystallization. `-~
Anal. Calc'd for Cl3Hl4N2: C, 77.68; H, 7.26; N, 13.52.
Found: C, 77.92; H, 7.33; N, 13.56.
The following pyrazoles of the structure:
CH
~ R~
(VI)
are prepared by the method of this example, employing the ap~
propriate 1,3--propanedione as a substitute for l-cyclopropyl~
,., ~
-3-phenyl-1,3-propanedione. The results of the process are
set forth in Table II below. The symbol ~ indicates al-
ternative positions of attachment of the methyl substituent.
- 14 ~
~037958
._ _ ... ~
~ ' ~ ~ ~ ~ '~ "'''' '1 ~, ~'', '
3 ~: Ul o h O "~
O O ~I C O h C 5,,
O.C~ S ~ ~ ~ O r~l ' bo~C~I ' '''~' :`" ''
~'
C~ Q~ ~ ~: R. ~ N h ,1:~
h cd ~ ~--1 ~ ~ ~a ~-I ~ ~
~5 b~ ~ ~3~ S ~1 0 3:
1~ O ~ d O ~ d ~ ~ : . :
O O ~ o :~ S h o a~
h ~ u~ h ~ ~ cJ ~ ,1 ~ . ~ -
.~ ~ b~ ~ S ~ '~ ~; ~ ~ 'cd `,' " ',,,
__= -_ _ ~D
s I o o I o I o I o
~;~ ~ ~ ~1 ~ ~ O
E~ P~ ~ C~ ~ S3 ~ .
_ ................... _ ~ _ ' ',. ~ ~ :
o~ O ,~ O , C- O
,'' . _ ._ __ . _ _
æl ~ ¦ [~
_ ._ __ ~
~ b m ~) b m~
_ ~ . l .. _- ~ :: '
;-
' ~ 1~
il)37958
O al .C q) ~: ~ ~ ' .C ~ . ~
~ V ~ ~a
~ 3 N 1~ ~--1 ~ ~ ~ ~ ~: N
Cl ~
æ ¦ ~3 ~
... .. , ",:
~1~
~. ... - ~
1 6
:-
. '. _ . _ ` ,. ! .; , ' ' ~ , .` . , : ' r . ~
~03795~
. ._ _
v I r ¦ O 1~
~:~ ::~ :~1 E; '`.~
O v V E O . ,
. ~: N v . `
~- -~ ~
~ G ~ ~ ~
-- 17
~ 1~37~5~
Other pyrazoles that can be prepared by the above
procedure employing the appropriate 1,3-propanediones are:
3,5-Dicyclohexenyl-l-methylpyrazole ~ :
3,5-Dibenzyl-l-methylpyrazole
3,5-Di-t-butyl-l-methylpyrazole
3,5-Dicyclopropyl-l-methylpyrazole ~ :
3-Benzyl-5-cyclohexenyl-l(and 2)-methylpyrazole
l-(and 2)-Methyl-3-(1-methylcyclohexyl)-5-phenylpyrazole
l-(and 2)-Methyl-3-(2-methylcyclohexy~-5-phenylpyrazole
.;~. . ~ , . .
- 10 3-Cyclohexyl-l(and 2)-methyl-5-(m-tolyl)pyrazole ~.
3-Cyclohexyl-5-(_-fluorophenyl)-l(and 2)-methylpyraæole
3-(p-Chlorophenyl)-5-cyclopentyl-l(and 2)-methylpyrazole `~
3-(_-Bromophenyl)-5-cyclohexyl-l(and 2)-methylpyrazole
3-Benzyl-l(and 2)-methyl-5-(p-methylthiobenzyl)pyrazole
15 3,5-(~,p'-Dichlorobenzyl)-l-methylpyrazole .
3-Cyclohexyl-5-(p-cyanophenyl)-l(and 2)-methylpyrazole
3-Cyclohexyl-l(and 2)-methyl-5-(m-trifluoromethylphenyl)pyrazole
3-(p-Anisyl)-5-n-hexyl-l(and 2)-methylpyrazole
3-Cyclohexylmethyl-l(and 2)-methyl-5-phenylpyrazole .
20 3,5-Di(cyclohexylmethyl)-l-methylpyrazole .~ -~
3-Cyclohexyl-5-ethyl-l(and 2?-methylpyrazole
3-Cyclopentylmethyl-l(and 2)-methyl-5-phenylpyrazole
Additionally, employing hydrazines other than methyl~
hydrazine, there are obtained~
3,5-Dicyclohexyl-l-ethylpyrazole
l-t-Butyl-~J5 dicyclohexylpyrazole ;~
3-(2-Carbomethoxyphenyl)-5-cyclohexyl-l(and 2)-methylpyrazole
3-(2-Carbomethoxyphenyl)-5-cyclopentyl-l(and 2)-methylpyrazole .
3-(2-Carboxyphenyl)-5-cyclohexyl-l(and 2)-methylpyrazole
3-(2-Carboxyphenyl)-5-cyclopentyl-l~and 2)-methylpyrazole
3-Benzyl-5-(2-Carboxyphenyl)-l(and 2)-methylpyrazole; and ;~
3-(2-Carbomethoxyphenyl)-5-cyclohexenyl-l(and 2)-methylpyrazole
- 18 _
1037~
- Example 3
- Preparation of ~-Cyclohexyl-1,2-dimethyl-phenylpyrazolium meth-
vlsulfate
; In a suitable reaction vessel, l-methyl-3(5)-cyclo-
hexyl-5(3)-phenyl pyrazole (8.o g., 0.033 mole) is dissolved
in dry toluene and warmed to ~65C. Dimethyl sulfate (4.5 g.,
0.035 mole) is then added and the mixture is brought to ref'lux.
Tlc (benzene) after 1-1/2 hours shows a small amount of pyra-
- ~ ~
zole remaining. After 2 hours the reaction mixture begins dar-
10 kening and heating is discontinued. On cooling a white solid
forins which is filtered and washed with dry toluene. This
tacky white solid is vacuum-dried at room temperature to give
a brittle solid. Hexane is then added and the solid broken up
and collected by filtration. me solid (6.3 g.l 50% yield) has
15 mp 48 - 51C. On exposure to air it becomes tacky (hygrosco-
pic). On analysis the following is noted. ;~ ~ -
Anal. Calc'd. for ClgH26N2SO4-H20: C, 56.24; H, 7.34; N, 7.29 ~
,
Found: C, 56.91; H, 7.33; N, 7.12.
Example 4
20 Preparation of 5-Cyclopropyl-1,2-dimethyl-3-phenylpyrazolium
methYl sulfate
A mixture of 3-cyclopropyl-1-methyl-5-phenylpyrazole
and 5-cyclopropyl-1-methyl-3-phenylpyrazole (33.1 g., 0.167
mole) and dry toluene (250 ml.~ are heated to reflux and ap-
25 proximately 25 ml. of solvent removed with a Dean Stark trap.
The solution is next cooled and dimethyl sulfate (18 ml. 9
0.193 mole) added. The reaction mixture is held at 100C. for ~ -
2.5 hours. A yellow brown oil is fo~ned which solidifies upon
cooling. The solid is removed by filtration and dried under
30 vacuum giving a cream colored solid (49.5 g., 91.5%) hav~g a
melting point equal to 163C. - 170C. whose analysis is as
follows:
.
- 19 -
~`` 1037~Sl~
Anal~ Calc 'd. for C15H20N2S4 C~ 55-54; H~ 6-22; N~ 8~64;
S, 9. 89 ~:
Found: C, 55.27; H, 6.23; N, 9.48; S, 9.99. : -~
Following the procedure of the above example, the ~ ;;
5 compounds in Table III below are prepared by substituting the - ~ .
appropriate l-methyl pyrazole for 3-cyclopropyl-1-methyl-5-
phenyl-pyrazole and having the generic formula:
CH3
, + CH3
R4 N~ : ~ :
~ - ~ CH3S04-
(VII) ;:
TABLE III
. _ _ ~~~ Melting Point __ ~ ;
~4 . (C- ) Appearance
___\ Off white .. ~
157 crystals ~ ;
l . Viscous brown
n-C5Hll oil oil -~ :
Additional pyrazolium compounds that can be prepared ~`~
by the procedure of Example 4 are as follows:
3-Cyclohexyl-1,2-dimethyl-5-(m-tolyl)pyrazolium methyl sulfate
3-Cyclohexyl-1,2-dimethyl-5-(o-fluorophenyl)pyrazolium methyl .
25 sulfate ~ :
3-(p-Bromophenyl)-5-cyclohexyl-1,2-dimethylpyrazolium methyl
sulfate
3,5-(p,p'-Dichlorobenzyl)-1,2-dimethylpyrazolium methyl sulfate ~
3-Cyclohexyl-1,2-dimethyl-5-(_-trifluoromethyl phenyl) pyrazol- ~: :
ium methyl sulfate
3-(p-Anisyl)-1,2-dimethyl-5-n-hexylpyrazolium methyl sulfate
3-Cyclohexyl-1,2-dimethyl-5-ethylpyrazolium methyl sulfate .~ ~ :
3,5-Dicyclohexyl-l-ethyl-2-methylpyrazolium methyl sulfate
~ ~
.,;
:: - . -.. . .. . .. ....
:~ ~379S~
3-(2-Carbomethoxyphenyl)-5-cyclohexyl-1,2-dimethylpyrazolium
methyl sulfate
3-(2-Carbomethoxyphenyl)-5-cyclopentyl-1,2-dimethylpyrazolium
methyi sulfate
The following pyrazo:les when reacted with dimethyl
sulfate, uslng the above method, y~eld products which are a ~ ~
mixture of methyl sulfate and hydrogen sulfate salts. In such ~ ;
instances, the products are converted completely to the iodides ;
and/or perchlorate salts by dissolving in water and treating
the same with saturated potassium (or sodium) iodide or dilute ; ~ ~
perchloric acid, respectively. For instance, utilizing either ~ ;
CH
(VIII)
where R4 is n-CllH23, (CH3)3C-, cycloheptyl-,
, : ~
CH3
or
~ ,
the methyl sulfate/hydrogen sulfate salts, when employing the
undecyl- and cycloheptyl groups, do not separate upon cooling
the reaction mixture. In these cases, the reaction mixture is
vacuum-stripped, the residue dissolved in water and used for
making the iodide and/or perchlorate without any solvent ex~
traction.
Example 5
Preparation of 5-Cyclopropyl-1,2-dimethyl-3-phenylpyrazolium
~erchlorate
An aqueous solution (500 ml.) containing 10 g. of
5-cyclopropyl-1,2-dimethyl-3-phenylpyrazolium methyl sulfate
_ 21 -
:................................... . ~ , ~
- ~037~5~ :
is extracted with ether. The aqueous layer is sepàrated and ~ I
treated w~th dllute perchloric acid (10 ml.) to give a solid.
- After stirring for one hour, the solid is removed by filtra-
- tion and dried to give a cream-colored solid (6.1 g., 60~) with
melting point 160C. to 161C. On analysis, the following is
obtained~
Anal. Calc'd. for C14H17ClN204: C, 53075; H, 5.48; N, 8.96;
Cl, 11.34
Found: C, 54.0; H, 5.40; N, 8.90; Cl, 11.48.
As noted in Table IV belowJ several exemplary per~
chlorates are prepared by the method as described in Example 5
above, using the appropriate pure, technical or crude 1,2-di-
methyl-3,5-substituted pyrazolium methyl sulfate salt aæ start-
ing material of the structure~
CH9
C10
( X ) !~
~ 20
.~ .. ,
, . . . -.~ :~
:
.
. ~ :
,'' ' ' ~
'
`
., , j
1 ;
:
- 22 - ~
.,.: . ... .... .. . .
~v37g~
'r ~
I h ~ ~ O ~ O
H ~ _ ~ _ _ _ _--
E u~ O
_ ... _ _ _ ~
"i 1~ ~ l~]
- 23 ~
;
10379~
Several com~ounds which can be prepared by the above
procedure are~
3,5-~ibenzyl-1,2-dimethylpyrazolium perchlorate
3-Benzyl-5-cyclohexenyl-1,2-dLmethylpyraæolium perchlorate
5 1,2-Dimethyl-3-(1-methylcyclohexyl)-5-phenylpyrazolium per-
chlorate ~~
3-Benzyl-1,2-dimethyl-5- ~-methylthiophenyl)pyrazolium per~
chlorate ;~
3-Cyclohexylmethyl-lJ2-dimethyl-5-phenylpyrazolium perchlorate
10 3,5-Dicyclohexylmethyl-1,2-dimethylpyrazolium perchlorate ~ ;
; 3-Benzyl-5-(2-carboxyphenyl)-1,2-dimethylpyrazolium perchlorate
3-Benzyl-5-(2-carbomethoxyphenyl)-lJ2-dimethylpyrazolium per- ;;
~ chlorate
; 3-Benzyl-5-(2-carbomethoxyphenyl)-1,2-dimethylpyrazolium per-
~ .
chlorate
In addition, compounds related to pyrazolium per-
chlorate salts were prepared, e.g., l-t-butyl-3,5-dicyclohexyl~
2-methylpyrazolium perchlorate salt.
Example 5
Preparation of 5-Cyclopropyl-1,2-dimethyl-3-phenylpyrazolium
iodide
,: ".' "' ~
A solution of 5-cyclopropyl-1,2-dimethyl-3-phenylpy-
razolium methyl sulfate (12.3 g.) dissolved in water (100 ml.)
is extracted with ether. The aqueous layer is separated and
. ~
25 treated with a saturated aqueous solution of potassium iodide. ~ -
After stirring for 0.5 hours, the solid is separated by filtra-
tion and dried to give a straw-colored solid (4.7 g., 36%) with
melting point lsooc. to 152C~ On analysis, the following is
noted.
Anal. Calc'd. for C14H17N2I: C, 49.42; H, 5.04; N, 8.24.
F~und: C, 4g.07; H, s.o6; N, 8.16.
Illustrative iodides in Table V below are prepared --
by the method as described above in Example 63 substituting
',
- 24 -
.
~ ~3 7
the appropriate ~yrazolium methyl sulfate salt for 5-cyclopro~
pyl-1~2-dimethyl ~-phenyl-pyrazollum methyl sulfate of the
structure: ;
:
CH3
R4 ~ N + ~ C~9
~ . .
R3 ~ :~
(XI) ~ ~
' ,' ~: ,
,,~
. :.
' ~
., ,', ~'
.,- ; ,
- 25 . ` ::~
. ";~ '
,. ! :
` '
. 30 .. :
~:
.' ,
:~ 25
~` :
~: -- ---- ----- : :;
~ ;~l~ ~ o
:~ ~
:; - 2 ~
; ~ .
- ;
.,
-': ' ~ -
.. - ~. .
7~
Xllustrative compounds which are prepared by the
above procedure are as follows:
3,5-Dicyclohexenyl-1,2-dimeth;yl~yrazollum iodide
3,5-Di-t-butyl-1,2-dimethylpyrazolium iodide
3,5-Dicyclopro~ylmethyl-1,2-dimethylpyrazolium iodide
3,5-Dicyclopropyl-1,2-dimethylpyrazolium iodide
1,2-~imethyl-~-(2-methylcyclohexyl)-5-phenylpyrazolium lodide
3-(~-Chlorophenyl)-5-cyclopentyl-lJ2-dimethylpyrazolium iodide
3-Cyclohexyl~5-( -cyanophenyl)-1,2-dimethylpyrazolium iodide
3-Cyclopentylmethyl-1,2-dimethyl-5-phenylpyrazolium iodide
3-(2-Carbomethoxyphenyl)-5-cyclohexenyl-1,2-dimethylpyrazolium
iodide ~
3-(2-Carboxyphenyl)-5-cyclohexyl-1,2-dimethylpyrazolium iodide ~ `
3-(2-Carboxyphenyl)-5-cyclopentyl-1,2-dimethylpyrazolium iodide
~xample 7
The selective postemergence herbicidal activity of
the compounds of the present invention is demonstrated by the
following tests, wherein a variety of monocotyledonous and di-
cotyledonous plants are treated with test compounds dispersed
in aqueous acetone mixtures. In the tests, seedling plants
are grown in jiffy flats for about two weeks. The test com-
pounds are dispersed in 50/50 acetone/water mixtures contain-
ing 0.5% of a polyoxyethylene sorbitan monolaurate surfactant ;~
in sufficient quantity to provide the equivalent of about 0.5
lb. to 4 lbs per acre of active compound when applied to the
` plants through a spray nozzle operating at 40 psi for a pre- ;
determined time. After spraying, the piants are placed on
- greenhouse benches and are cared for in the usual manner, com-
mensurate with conventional greenhouse pract~ces. Five weeks
after treatment, the seedling plants are examined and rated
according to the rating system provided below. The data ob-
tained are reported in Tables VI and VII below where it can
be seen that the compounds are highly effective for the con- --
.. ;,~ .
~ 27
~.0379S~ `~
trol of many broadleaf weeds and undesirable grass plants.
% Di~fe.rence in Growth
Rating System
o - no effect O
: 1 - possible effect 1 - 10 ~
2 - sl~ght effect 11 - 25 ~ ~;
3 - moderate effect 26 - 40
5 - definite injury 41 - 60
6 - herbicidal effect 61 - 75
7 - good herbicidal effect 7~ - 90
8 - approaching complete kill 91 - 99 `
9 - complete kill 100
4 - Abnormal growth, that iSJ a definite physiological malfor-
mation but with an over-all effect less than a 5 on the .
rating scale.
lBased on visual determination of stand, size, vigor, chlorosis, .~
;: growth malformation and over-all plant appearanceO ~ ?
Plant Abbreviation: ..
; ~
MU - Mustard :~
(Brassica kaber)
PI - Pigweed ::
(Amaranthus retroflexus) :
BA - Barnyard grass .
(Echinochloa crusgalli)
. CR - Crabgrass
- (Digitaria sanguinalis) :~
WO - Wild Oats : ~
:: (Avena fatua) :.
- WH - Wheat ` :~
: (Triticum aestivum) .- -,
MG - Morning glory
(Ipomoea purpurea)
. .~
Barley - (Hordeum vulgare)
3o
VL - Velvetleaf
: (Abutilon theo~hrasti) : ~.. .
~ FO - Green Foxtail .
il (Setaria viridis)
! RI - RiC e
; (Oryza sativa) .::.
28
f
~03 ~'~S~ ~ `
~ . . _ . _ __. , . . : .
~ ~ o o ~ ,t ,, ~ o o C~ ~
_ _ _ ............... . ~
. 3 O O O O O O O O O t~ O O : -
.. ~ . .. .___ ; ~,
P~ O O O O O O O O O O O O
,~ ~__ ~ ._ ._. . _ . . ~ ~ `
:' ~ O O O ~ O~ ~) ; U~ `,':~,; "`
_ . .__ , .__ ~
O O O O O O O O O O ~ O O ' ~'
. -
_ ' ~4 ~ 0 O O O ~ O O ~O ~D
.. ~ . ... _ '`~
? ~ C~l O O O O O O O O 0~ C~l
. ! ~ . __
¢ P~ O O O O O O O O O ' ~0 C-- u~ .
C) H _ - . . ;~;
.,.', E-~ ~ O O O o~ _ _ ~ ` :~
`..' ~ ~ O O O O O O ~1 0 0 I I ~ ~,`','' ~``~;' `~'
~ . _ . . , - _, _ .
.' E~ ~ O ' O O O~ cr~ ~ ~ o~ 0 '~
~ ~ ~ ~ _ . - ~ ~, ._ `~
P~ m ~ o o o o o o o o o o o o
~t~
- 2 9
:. . .~
~7~5~
..... , . _.......... .. ,.. _ ...... ` .
O O o ~ o~ o o~ ~o u~
.. _ ......... . . `~
:3 o o o ~ o o ~ C~ ~o
. . j - . _ . . . ~ ~
~ I o o o o C) o o o o o o o ,.
... _ ...
.' ~: ~ o o ,1 o o ,, o o CO ~ ~ `'
.~ ~ ,~
~o o o o o o o ,, o o
. ~ . Q ... __ _ ............ ~ ~ ~
:., ~ ' C~ O O ~1 ~1 0 ~ ~ O O~ ~O O "'.~
:~, .._. _ . ~ . ._ ~
~1 ~) 0 U~ O CO U~ ~ ~ O O ~ ~ ~ , ~
.. ~ . ... . . .. ,`:
H ¦ ¢ p:l L~ O O H O O C~l O O Lr~ H 0 .;
, ~ ¦ ~a H ., .~ . . ...
1~ ¦ ~ P~ ~---- O O CO C~l O Ir~ O O 0~
h . . __ . ._ .
~,, O ~ ~ O O r-l O O ~ O O C~ '~
bD . ..._ . .. __
O ~ ~ Il~ ~-1 0 ~ O O O~ ~ ~9 '~
:. tQ h ~ __ _ ... . . ._ __ _ .
P~ ~ o o o o o o o s::~ o o o o
__ .. _ .. _,
., ~_ ~ ~ ~ ~ ~ ~1 ~ ~ ~i ~ .,/
- . . .- - .- . ~ ;;'~: `; ~ `,
. I O H H t-~ H ~C . -.: :. .
_ H H ~1 ~C
o ~31~I ,~z
, .~ ~3 .'.. '''' :'`':'
', . . ~` ....................... ..`. .
. .......................... ~ .
. .
- 30 `~ :~
:' .
~l~379~ ~
P r~
o ~c~ o o Lr~ oo ~ ~ :
~__ . .
O O W ~ O ~ ~ O In ~ O
._ __ . . , . ._ ;~
~ ,, ~ ~ ~ ~ ~ ~ ,. ~ ~ ,``~
.. __~ ~ . .,~ `~
.' ~ o C~l o ~ o o Lr~ ~ ,, CO ~ ~ -~,
. ~ _. . . `~
. ~ ~ ~ ~ ~ ~ ~
_. + ._ I __ . ~ ~
,. . ~ ~ 0 ~ ~ ~ ~ ~ 03 ~ ~ .,~
~ I ........ ~ .. ~
~' ~ ~ ~ I O O O ~ CtJ ~ ~1 ~ 1 ',' ~'
C '~J - H ! ~ . ` `; ~
.~ O ~1 L~ O a~ ~ 1~ tS~ ~O ~ Cl~
H h . ~ . ~ . _ _ ... . ___ .. _ .___
~ ~ ~ ¦ ~ ~ u~ O O C~J O O C'J ~3 0
3 ~c __ _ _
E ~ ~ ~ ~ 1~ C~~ O~
~ i --.. __ .__ ~ '' ~;:
O ~ O O O OO O O O O O O O ', .~ ~;
-~ T~ `
- 31 - i -
-.
1~379Sl~ ~
.
:- . -- : :
~ ,, ~ C~ ~ o. : ~
. . .. _ . . . ~ ~ .
'.- o I o o o ~ 0 0~ t- CO o o o -; ;
-: H . . .
.''~ Ir; ~ ~ O O O O~ Lr~ u~ O O O ': -
. . . . _ - 'i : ~; ?
~' ~ ~ ~ ~1 L~ ~ ~ ~ ~O O -~,'
.. o . ._~ --
. , :3 O O O ~ ~ ~~ 0 C- ` ``
O ._ ,''~
.. ~ ~ 0 0 ~`J O O0 ~1 ~1 ~ O O
_ ~ .. _ . .
~ O~ O O O O~ ~ ~ O O O- `'`,~
~o , ~ . - _......................... '`'~
~ ~ ~ O ~ O O ~- ~ ~ O O O j~
r~ I ~~; ~ _ , .
: ~ I ~ (). o ~ o~ a-3 ~ O O 0~ ~O O a~ 0~ C>
¦ h ._~
l ~ ~ l l l o o o
H ¦ S~ . ~ ; ~ ` -
- .~ ¦ h ~ 0~ ~0 ~0 ~ O O C~ 0 CU O
~ h :~, . . ........ `' ~' ;'
.' a~ ~ ~u O O O O O O o o ~ o o_ ~ "
. h ~ . ~ ~ ~ - :
1 J ~ ~ ~ ~ rl "
_ ~ ~ _ _~
. I ~ ~ ~ O ~ ~ H
.j ~i O X r~ ~ ~1 ~ f~ , ~
~ o ~ 3 x I 1 3 o ~
.3 c~ I ~ ~z- v r~ ~ `` ~:
~ ~_ I x ~- c) ~ ~ \~= ~ ~: ~
Ib 1~
` .... ----~ - t-- : ..
- 3~
:; ~
. ,.. .. . . ...... . . ~ . ... ... ; ... . .. .. ~. .... ;. . . . . .
-` 10~7~5~
Example 8
The preemergence activity of the compounds of the
present invention is demonstrated by the following tests where- -
in a 50~50 acetone/water mixture containing 0.5~ by volume of
a polyoxyethylene sorbitan monolaurate surfactant and suffici-
ent test compound ~rovide 10 pounds per acre of said compound
when the mixture is applied to pots planted with seeds o~ test
plant species.
The pots are prepared the day of herbicide treatment
by putting 100 ml. of soil in each plastic pot as a base, then
morningglory, tomato, wild oats and nutsedge seeds are placed
on this base and covered with 50 ml. (3~8 to 1/2 inch) of soil.
Seeds of each of the other 8 plant species identified below are
separately mixed with soil and 50 ml. of the soil seed mix ad~
ded to the pot. The pots are then tamped to level the soil and "
the soil is prewetted with water prior to herbicide application.
This prewetting insures that the herbicide treatment solution
spreads evenly over the surface of the pot and protects the `~
weed seeds from acetone injury. Each of the 12 weed species
- 20 is contained in a separate pot. The pots are then arranged in
10 x 12 inch flats prior to chemical treatment. --~
The planted pots are treated with 5 ml. of test solu~
- tion and then placed on benches in the greenhouse. Pots are
watered after treatment and held in the greenhouse for three ~;~
weeks at which time the results are recorded, as reported be~
low in Table VIII.
Plant S~ecies Used in Preemergence_Herbicide Evaluation
Common Name Abbreviation Scientific N~me
Nutsedge NS Cyperus rotundus
30 Lambsquarters LA Chenopodium album
- ~ild Mustard MU Brassica kaber
Pigweed PI Amaranthus retroflexus
Ragweed RW Ambrosia artemisiifolia
- 33 -
.~ . , .
~37~S~
Morningglory MG Ipomoea p_}~
Barnyardgrass BA Ec nochloa crus~alli
Crabgrass CR Digitaria sanguinalis ~,
. Green Foxtail FO Setaria viridis ~:
5 Wild Oats WO Avena fatua
: Tomato TO Lyco~ersicon esculentum
Velvetleaf VL Abutilon theoPhrasti ~:
The rating system used in these tests is the same as -
- described in Example 7 above.
.
. .
~,
` `~
-. 20 `~ `
.. ~ - .
.;-~'. ;'' .''
^
' . ~
~.
.' ,, ~ ~
: _ 3~ _
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;
r -
:`
:: ~ ~ - ~
~ o ! C I ~ ;
.. .. ... Ln . ~. o
~ 3 O o ~ ~ `` :~ ~
.. _ ._ _ __ . '`;
~ c~l ao . ~ ~ '~
.' . _ _................... , '`'~
, ~; ao ~ o~
~ _.. _ . .
,~ ~ ao ~ t- ,',' :: -
._ . .'':~
~ ~: U~ O ~ ~ ,'
.. ~1 ,,,"
-.,, q; ~ O . O U~ `'."'~`~
.1 m ~ ~
~D O ~ ~<"~' '~.: ,.-
. ~ æ~ r (~17 2~ r~3J`
mr
- ~ 3
37~S~
_ __ _
1~
~ ~ ~ ;~
_ ~ . .
o ~ . o ' ~` ''~ ''
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3b
-
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. . _ .
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-................. o Cr~ ~ ~ " ::
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3.~ 3 5~
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:~ _ ~ . _ ; ~ ~`
- 3 7 ~;
.. . . . . . .
