FLUORINE IN THE LIFE SCIENCE INDUSTRY
120
CHIMIA 2004, 58, No. 3
Scheme 5. Sulfonyl ureas derived from 3-fluoro-2-methoxy-carbonyl-benzenesulfonamide
3. Results and Discussion
emergence tests, plants were cultivated in
plastic pots of 8.6 cm diameter containing
loamy sand with about 1.2% humus as the
substrate. The test plants were sown, grown
in the test pots to a height of 4–12 cm and
then treated with the test compound in a
spray chamber at a rate of 0.25–0.5 kg/ha
a.i. (active ingredient) for the benzoxazi-
nones and 62.5 g/ha a.i. for the sulfonyl-
ureas, formulated as emulsion concentrates.
The number of replicates was one and, for
comparison, four untreated control pots
were included in each test. After the
application, the test plants were kept for
18–20 days at 18–27 °C, during which pe-
riod the plants were maintained and their
reaction to the individual treatments was as-
sessed and recorded. Injury to the plants
was assessed on a scale from 0 to 100 in
comparison to the untreated controls, with
0 denoting no damage and 100 denoting
complete destruction of at least the visible
plant parts.
better parabolic relation with log P = 4.3
as the optimum.
3.1. Structure–Activity Relationship
(SAR)
3.1.1. Benzoxazinones
What can be clearly seen is the effect of
several fluorine atoms adding to the over-
all lipophilicity compared with the unsub-
stituted standard 28 with a log P = 3.3. In-
troducing only one fluorine atom into the
anthranilic acid moiety of the standard re-
sults in log P = 3.2 (compound 2). As ex-
pected, the lipophilicity difference in both
cases is small and shows once again the
similarity of hydrogen and fluorine in a
bioactive molecule as far as size and
lipophilicity are concerned. But fluorine,
being much more electronegative, appar-
ently binds better to the enzyme, resulting
in higher activity. In fact, this compound
turned out to be the most active derivative.
At 250 g/ha, 5-fluoro-2-phenyl-4H-3,1-
benzoxazin-4-one controlled numerous
weed species and possessed excellent se-
lectivity in several crops. Results were con-
firmed by field trials at rates of 0.5 kg/ha
(Table 4).
With these benzoxazinones available,
standard screening trials were conducted
in the greenhouse with post-emergence
treatment of different crops containing
broadleaf weed species at 0.5 kg/ha ai,
formulated as a suspension concentrate.
While chlorine (Table 2) induces a loss of
activity – except in the 5-position, where
it is equivalent to the standard – a contin-
uous increase in activity was observed as
the hydrogens were replaced stepwise by
fluorine on passing from the 7- to the 5-
position. The 8-fluoro derivative was
weaker than the parent compound, but
surprisingly the 5-fluoro derivative
proved to be about three times as active as
the standard. Table 3 shows the average
activity on seven plant species on a scale
of 0 to 100 and the lipophilicity (log P)
measured by standard HPLC procedure.
While dichloro 29 for both R1 and R2 or a
combination of nitro and chlorodifluo-
romethoxy 33 reaches only medium activ-
ity with less than 50%, high activity is ob-
served for chloro and pseudohalide side-
chain substituents connected to fluorine-
or chlorine-substituted anthranilic acid.
When phytotoxicity is correlated with
lipophilicity (Fig. 1), three different clus-
ters can be identified: 5-fluoro-3,1-ben-
zoxazine-4-ones and their corresponding
5-chloro derivatives, each with fluorine
side chains, as compared to the unsubsti-
tuted bentranil 28. The 5-fluoro-3,1-ben-
zoxazin-4-ones show only a very small
range of lipophilicity with 3.7 as the opti-
mum, while the chloro derivatives show a
2.5.2. Test Species
The following plant species were used:
Broadleaf weeds: velvet leaf (Abuthilon
theophrasti), redroot pigweed (Amaran-
thus retroflexus), hairy beggarticks
(Bidens pilosa), common lambs-quarters
(Chenopodium album), bengal commelina
(Commelina benghalensis), florida beggar
weed (Desmodium tortuosum), wild poin-
settia (Euphorbia heterophylla), cleavers
(Galium aparine), annual mercury (Mer-
curialis annua), chamomile (Matricaria
spp.), tall morning glory (Pharbitis pur-
purea), ladysthumb (Polygonum persi-
caria), hemp sesbania (Sesbania exaltata),
wild mustard (Sinapis arvensis), black
nightshade (Solanum nigrum), and maize
(Zea mays).
3.1.2. Sulfonylureas
The herbicidal activity of the Classic®
analogues was compared on six broadleaf
weeds in the greenhouse at an application
rate of 62.5 g/ha (Fig. 2). Derivative 27B
achieved the highest activity with a sum of
585, but was followed very closely by the
fluoro and chloro derivatives 27A and 27C
with sums of 560 and 561 respectively. The
difference in selectivity is critical.
While the unsubstituted SU has no se-
lectivity at all on maize and the chloro com-
pound still produces 50% damage on
maize, the fluoro derivative is much safer
and shows only 10% damage three weeks
after treatment – damage that later assess-
ments show to have grown out.