Highly fluorinated 2,2′-biphenols and related compounds: Relationship between substitution pattern and herbicidal activity

Article abstract of DOI:10.1021/jf401081g

A broad range of halogenated 2,2′-biphenols was tested for applicability as crop protection agents. The activity of these compounds toward four typical pest plants was observed after application by spraying of diluted solutions. Despite their rather simple structure, it was found that the studied compounds reveal a surprisingly high herbicidal impact. To gain a better understanding of the structure-activity relationship, specific sites of the molecule were chemically modified and the core structures thus gradually changed. The influence of the substitution pattern on the herbicidal properties is discussed, and conclusions on the active site of the biphenol structure are drawn. It was observed that type and position of the halogen substituents have a significant influence on the activity of the core structure. The hydroxy functionalities play a crucial role for the effectiveness of the tested compounds. Because the blocking of the hydroxy moiety leads to dramatically deteriorated performances, the presence of these functionalities on the aromatic ring seems to be indispensable.

Full text of DOI:10.1021/jf401081g

Article
pubs.acs.org/JAFC
Highly Fluorinated 2,2′-Biphenols and Related Compounds:
Relationship between Substitution Pattern and Herbicidal Activity
Robert Francke,†,# Rudiger Reingruber,§ Dieter Schollmeyer,† and Siegfried R. Waldvogel*,†
̈
†Institute for Organic Chemistry, Mainz University, Duesbergweg 10-14, 55128 Mainz, Germany
§BASF SE, GVA/HC − A030, 67056 Ludwigshafen, Germany
ABSTRACT: A broad range of halogenated 2,2′-biphenols was tested for applicability as crop protection agents. The activity of
these compounds toward four typical pest plants was observed after application by spraying of diluted solutions. Despite their
rather simple structure, it was found that the studied compounds reveal a surprisingly high herbicidal impact. To gain a better
understanding of the structure−activity relationship, specific sites of the molecule were chemically modified and the core
structures thus gradually changed. The influence of the substitution pattern on the herbicidal properties is discussed, and
conclusions on the active site of the biphenol structure are drawn. It was observed that type and position of the halogen
substituents have a significant influence on the activity of the core structure. The hydroxy functionalities play a crucial role for the
effectiveness of the tested compounds. Because the blocking of the hydroxy moiety leads to dramatically deteriorated
performances, the presence of these functionalities on the aromatic ring seems to be indispensable.
KEYWORDS: fluorinated compound, phenol, comparative biological activity, pesticide, crop protection
the worldwide inventory of pesticides containing miscella-
neously halogenated compounds as active material has grown
steadily in the past decades.9,10 The current trend indicates
clearly that especially fluorinated products will become more
and more important.
INTRODUCTION
■
For a long time, synthetic postemergence herbicides have been
frequently employed to selectively control weeds, as manual
removal is time-consuming and expensive and often leads to
damage of the crop or ornamental plant.1 The use of highly
effective chemical control of weeds not only has replaced
manual and mechanical weed control, it also increased
productivity and has enabled the development of larger farm
sizes and an improved subsistence for farmers.2 There is still a
high demand for new products in this field, because only a few
selective postemergence weed control agents for the sufficient
supply of the constantly growing world population are available.
One of their major properties has to be the maximization of the
crop yield along with the quality of the crops.1
Particularly, fluorinated 2,2′-biphenols might be of interest
for crop protection or pharmaceutical applications. Finger et al.
studied the biological activity of a series of fluorinated aryl
compounds.3 Their promising results prompted us to perform
biological tests of a set of fluorinated 2,2′-biphenols and some
related compounds. In this context, a high herbicidal impact
was found. Consequently, we performed several modifications
of this structural motif to learn more about the correlation
between substitution pattern and impact of the substances on
several types of weeds. Generally, such fluorinated aromatic
compounds are highly stable under extremely harsh conditions,
as the C−F bond is of high strength and the electron-
withdrawing properties can prevent aromatic rings from
metabolic4,5 or electrochemical oxidation.6,7 As the spatial size
of a fluorine atom is similar to a hydrogen atom, a replacement
of one or more hydrogen atoms by fluorine does not lead to a
steric distortion of a molecule. This can lead to an
incorporation of the fluorinated compound into the life cycle
of diverse organisms.8 Moreover, the specific lipophilicity and
metabolic stability of fluorinated structures lead to significant
application in drug development and pharmaceutics.5 Hence,
MATERIALS AND METHODS
■
Synthesis of the Tested Compounds. For the NMR measure-
ments, chemical shifts (δ) are reported in parts per million relative to
traces of CHCl3, CD3OD, or DMSO in the corresponding deuterated
solvents and to CCl3F as an external standard for 19F NMR,
respectively. Coupling constants (J) are presented in hertz. The
supplementary crystallographic data for this paper can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif (CCDC 905686, compound 5c).
Halogenated 2,2′-biphenols and 2,2′-bisanisoles were prepared
according to procedures reported in the literature.11,12 The
preparation of the modified compounds was performed as follows:
3,3′-Dichloro-5,5′-difluoro-2′-hydroxy-2-methoxybiphenyl (5a).
3,3′-Dichloro-5,5′-difluoro-2,2′-bisanisole12 (1.70 g; 5.33 mmol) in
20 mL of dry dichloromethane was placed in a Schlenk flask under
argon and cooled to −78 °C. To the mixture was added dropwise
under stirring 0.89 g of BBr3 (3.55 mmol) in 15 mL of
dichloromethane. After 2 h, the solution was allowed to warm to
room temperature and stirred overnight. The mixture was fractionated
by addition of water and the aqueous layer extracted with
dichloromethane (2 × 40 mL). The combined extracts were dried
over MgSO4 and concentrated under reduced pressure. The desired
product was isolated by column chromatography (cyclohexane/ethyl
acetate 95:5, RF = 0.21, flash gel, 1.5 bar) in 39% yield (0.63 g, 2.06
1
mmol, colorless crystalline solid): mp 74 °C; H NMR (300 MHz,
CDCl3) δ 7.20 (dd, J = 7.7, 3.1, 1H), 7.17 (dd, J = 7.7, 3.1, 1H), 6.95
Received: March 10, 2013
Revised: April 30, 2013
Accepted: May 4, 2013
Published: May 5, 2013
© 2013 American Chemical Society
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(dd, J = 8.5, 3.1, 1H), 6.94 (dd, J = 8.5, 3.1, 1H), 6.44 (s, 1H), 3.61 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 158.4 (d, J = 247.4), 155.9 (d, J =
242.9), 149.1 (d, J = 3.4), 145.7 (d, J = 2.9), 132.8 (dd, J = 9.2, 1.6),
129.3 (d, J = 11.4), 125.9 (dd, J = 8.5, 2.2), 122.7 (d, J = 11.0), 117.8
(d, J = 25.4), 117.1 (d, J = 24.3), 116.9 (d, J = 24.5), 116.2 (d, J =
23.7), 61.7 (s); 19F NMR (377 MHz, CDCl3) δ −115.7 (m), −121.7
(m). HRMS calcd for C13H9F2Cl2O2, 304.9948; found, 304.9955.
Elemental analysis (C13H8F2Cl2O2, M = 305.10) calcd, (%) C 51.18, H
2.64; found (%) C 51.05, H 2.53. Forty percent of the starting material
was recovered (0.68 g, 2.13 mmol, RF = 0.55) and the 2,2′-biphenol 4a
was obtained after elution with pure ethyl acetate (0.25 g, 0.86 mmol,
16%).
was removed under reduced pressure. The product mixture was
separated with column chromatography (cyclohexane/ethyl acetate
95:5). 7a was obtained in the first fraction as a light brown solid (RF =
0.21), which was sublimated to afford 1.90 g (5.72 mmol, 44%) of the
colorless crystalline product: mp 104 °C; 1H NMR (300 MHz,
CDCl3) δ 6.91−6.94 (m, 1H), 6.85−6.88 (m, 1H), 6.83−6.79 (ddd, J
= 8.4, 3.0, 1.7, 1H), 6.73−6.69 (ddd, J = 8.8, 3.1, 2.0, 1H), 4.60 (d, J =
2.8, 2H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 168.4 (s), 157.3
(dd, J = 245.8, 12.4), 155.5 (dd, J = 241.5, 11.3), 153.8 (dd, J = 248.2,
12.8), 152.4 (dd, J = 245.8, 12.7), 138.6−138.7 (m), 138.4−138.5 (m),
130.8−130.9 (m), 126.9−127.1 (m), 113.7 (dd, J = 23.5, 3.2), 112.1
(dd, J = 23.2, 3.7), 105.3 (dd, J = 26.7, 24.0), 104.6 (dd, J = 26.3, 22.9),
83.7 (s), 69.3 (d, J = 8.8), 27.9 (s); 19F NMR (377 MHz, CDCl3) δ
−116.3 to −116.5 (m), −120.6 to −120.9(m), −127.3 to −127.5 (m),
−130.8 to −130.9 (m). HRMS calcd for C18H16F4O4Na, 395.0882;
found, 395.0893. Elemental analysis (C18H16F4O4, M = 372.21): calcd
(%), C 58.07, H 4.33; found (%), C 57.96, H 4.30. In the second
fraction, 7b was contained, whereas unconverted biphenol 4b was
recovered in 31% yield in the third fraction (0.93 g, 3.60 mmol, RF =
0) after elution with ethyl acetate.
3,3′,5,5′-Tetrafluoro-2′-hydroxy-2-methoxybiphenyl (5b). To a
mixture of 1.28 g (4.97 mmol) of 3,3′,5,5′-tetrafluoro-2,2′-biphenol
(4b),12 0.75 g (5.46 mmol, 1.1 equiv) of K2CO3, and 15 mL of DMF
was added dropwsie 0.70 g (4.97 mmol) of methyl iodide. After
overnight stirring, ammonia solution (10% in water) was added, and
the aqueous layer was extracted two times with 50 mL of tert-butyl
methyl ether (TBME). The organic layer was washed three times with
water and dried over MgSO4. After removal of the solvent under
reduced pressure, the product mixture was separated using column
chromatography (cyclohexane/ethyl acetate 9:1, RF = 0.20, flash gel,
1.5 bar). The desired product was yielded as a colorless crystalline
2,2′-Di((tert-butyloxycarbonyl)methoxy)-3,3′,5,5′-tetrafluorobi-
phenyl (7b). 7b was obtained in 20% yield as a colorless crystalline
solid (1.15 g, 2.36 mmol) after conversion of 4b with 1 equiv of tert-
1
1
butyl-2-bromoacetate (RF = 0.11, see above): mp 98 °C; H NMR
solid (0.50 g, 1.84 mmol, 37%): mp 84 °C; H NMR (300 MHz,
(300 MHz, CDCl3) δ 6. 86 (ddd, J = 11.3, 8.2, 3.1, 2H), 6.8 (ddd, J =
8.4, 3.0, 1.7, 2H), 4.43 (s, 4H), 1.40 (s, 18H); 13C NMR (75 MHz,
CDCl3) δ 167.4 (s), 157.4 (dd, J = 244.7, 12.0), 154.6 (dd, J = 249.0,
12.7), 140.3 (dd, J = 11.2, 4.1), 131.6−131.8 (m), 113.0 (dd, J = 23.3,
3.5), 104.9 (dd, J = 26.5, 23.4), 81.9 (s), 70.4 (d, J = 5.8), 27.9 (s); 19F
NMR (377 MHz, CDCl3) δ −116.7 (ddd, J = 8.4, 8.4, 4.2), −125.8 to
−126.0 (m). HRMS calcd for C24H26F4O6Na, 509.1563; found,
509.1549. Elemental analysis (C24H26F4O6, M = 486.45), calcd (%): C
59.26, H 5.39; found (%), C 59.12, H 5.01.
2′-Hydroxy-2-carboxymethoxy-3,3′,5,5′-tetrafluorobiphenyl (6a).
One gram (2.69 mmol) of 7a was dissolved 6 mL of TFA and stirred
overnight. The precipitated product was filtered off, recrystallized from
boiling water, and sublimated (10−3 mbar, 120 °C). The product was
obtained as a colorless crystalline solid (0.77 g, 2.44 mmol, 91%): mp
155 °C; 1H NMR (400 MHz, CD3OD) δ 7.06 (ddd, J = 11.5, 8.4, 3.1,
1H), 6.98 (ddd, J = 11.1, 8.4, 3.1, 1H), 6.92−6.86 (m, 1H), 6.85−6.81
(m, 1H), 4.55 (s, 1H); 13C NMR (101 MHz, CD3OD) δ 170.8 (s),
157.7 (dd, J = 243.0, 12.3), 155.0 (dd, J = 247.7, 13.2), 154.7 (dd, J =
238.9, 11.7), 151.4 (dd, J = 242.0, 12.6), 140.2 (dd, J = 11.3, 3.9),
138.9 (dd, J = 15.2, 3.5), 132.6 (d, J = 9.6), 126.5 (d, J = 9.1), 112.7−
112.9 (m), 112.2 (dd, J = 23.4, 3.5), 104.1 (dd, J = 27.2, 23.8), 103.3
(dd, J = 27.1, 23.4), 69.3 (s, J = 8.8); 19F NMR (377 MHz, DMSO-d6)
δ −117.5 (m), −123.2 (dd, J = 9.4. 9.4), −126.0 (d, J = 11.9), −130.9
(d, J = 11.3). HRMS calcd for C14H8F4O4Na, 339.0256; found,
339.0258. Elemental analysis (C14H8F4O4, M = 316.20): calcd (%), C
53.18, H 2.55; found (%), C 52.88, H 2.53.
CDCl3) δ 6.99−6.88 (m, 2H), 6.88−6.76 (m, 2H), 6.34 (s, 1H), 3.77
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.3 (dd, J = 246.4, 12.2),
157.3−150.4 (m), 140.6 (dd, J = 12.2, 3.9), 138.4 (dd, J = 13.3, 3.7),
132.1−132.3 (m), 126.6−126.7 (m), 113.1 (dd, J = 23.6, 3.5), 112.1
(dd, J = 23.4, 3.7), 105.3 (dd, J = 26.7, 23.2), 104.8 (dd, J = 26.6, 22.9),
62.5 (d, J = 4.4); 19F NMR (377 MHz, CDCl3) δ −114.5 (m), −120.4
(m), −125.6 (m), −131.0 (m). HRMS calcd for C13H8F4O2Na,
295.0358; found, 295.0357. Elemental analysis (C13H8F4O2, 272.20)
calcd (%), C 57.36, H 2.96; found (%), C 57.19, H 2.70. Furthermore,
0.40 g (1.40 mmol, 28%) of the corresponding bisanisole was isolated
after column chromatography (RF = 0.57). Unreacted starting material
was recovered by neutralization and 2-fold extraction of the aqueous
layer (0.31 g, 1.20 mmol, 24%).
5,5′-Difluoro-2′-hydroxy-3,3′-dimethyl-2-methoxybiphenyl (5c).
Methyl iodide (0.83 g; 5.83 mmol) was added dropwise at 0 °C to
a mixture of 1.46 g (5.83 mmol) of 5,5′-difluoro-3,3′-dimethyl-2,2′-
biphenol (4c),12 0.80 g (5.83 mmol) of K2CO3, and 20 mL of DMF.
The mixture was allowed to warm to room temperature and stirred for
3 h. Then ammonia solution (10% in water) was added and the
aqueous layer extracted two times with TBME (30 mL). The organic
layer was washed three times with water and dried over MgSO4, and
the solvent was removed under reduced pressure. The desired product
was isolated using column chromatography (cyclohexane/toluene 1:1,
flash gel, 1.5 bar, RF = 0.46). After sublimation (10−3 mbar, 60 °C),
1.05 g of 5c (3.97 mmol, 68%) was obtained as a colorless crystalline
solid: mp 57 °C; 1H NMR (300 MHz, CDCl3) δ 7.05 (s, 1H), 6.88−
6.95 (m, 2H), 6.87−6.81 (m, 2H), 3.50 (s, 3H), 2.34 (s, 3H), 2.31 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 159.2 (d, J = 243.8), 156.0 (d, J =
244.0), 150.3 (d, J = 2.7), 147.8 (d, J = 2.2), 133.5 (d, J = 8.5), 132.5
(d, J = 8.6), 129.1 (d, J = 8.0), 125.8 (d, J = 6.4), 117.4 (m), 116.0 (d, J
= 23.3), 113.9 (d, J = 23.2), 61.3 (s), 16.9 (s), 16.3 (s); 19F NMR (377
MHz, CDCl3) δ −117.7 to −118.1 (m), −124.6 to −124.8 (dd, J =
9.0, 9.0). HRMS calcd for C15H15F2O2, 265.1040; found, 265.1041.
Elemental analysis (C15H14F2O2, M = 264.27), calcd (%) C 68.17, H
5.34; found (%), C 67.77, H 5.39. Aside from 5c, the corresponding
2,2′-bisanisole (0.16 g, 0.57 mmol, 10%, RF = 0.34) and unreacted
starting material (0.82 mmol, 14%, RF = 0.05, eluted with ethyl
acetate) were isolated after column chromatography.
2,2′-Di(carboxymethoxy)-3,3′,5,5′-tetrafluorobiphenyl (6b). 7b
(0.80 g; 1.64 mmol) was dissolved in 5 mL of TFA and stirred
overnight. The precipitated solid was filtered off, recrystallized from
boiling THF, and dried overnight (10−3 mbar, 100 °C). The product
was obtained as a colorless crystalline solid (0.58 g, 1.55 mmol, 94%):
1
mp 253 °C; H NMR (300 MHz, DMSO-d6) δ 7.39 (ddd, J = 11.8,
8.8, 3.0, 2H), 7.10−7.02 (m, 2H), 4.51 (s, 4H); 13C NMR (75 MHz,
DMSO-d6) δ 169.7 (s), 156.8 (dd, J = 242.1, 12.6), 154.2 (dd, J =
247.1, 13.6) 140.1 (dd, J = 11.2, 3.9), 131.3−131.5 (m), 113.4 (dd, J =
23.6, 3.3), 105.3 (dd, J = 27.0, 23.9), 69.56 (d, J = 5.6); 19F NMR (377
MHz, DMSO-d6) δ −117.2 (ddd, J = 8.8, 8.8, 4.0), −126.2 (dd, J =
12.0). HRMS calcd for C16H10F4O6Na, 397.0311; found, 397.0325.
Elemental analysis (C16H10F4O6, M = 374.24) calcd (%), C 51.35, H
2.69; found (%), C 51.18, H 2.46.
2′-Hydroxy-2-(tert-butyloxycarbonyl)methoxy-3,3′,5,5′-tetra-
fluorobiphenyl (7a). A mixture of 3 g (11.61 mmol) of 3,3′,5,5′-
tetrafluoro-2,2′-biphenol (4b),12 1.62 g (11.61 mmol) of K2CO3, 2.27
g (11.61 mmol) of tert-butyl-2-bromoacetate, and 20 mL of DMF was
stirred for 24 h at room temperature. Then it was fractionated by
addition of water and TBME and the aqueous layer extracted two
times with TBME (2 × 100 mL). The combined organic layers were
washed three times with water and dried over MgSO4, and the solvent
Greenhouse Experiments. The culture containers used were
plastic flowerpots containing loamy sand with approximately 3% of
humus as the substrate. For the postemergence treatment, the test
plants (see Table 1) were first grown separately, and several of the
seedlings were transplanted into the test containers a few days prior to
treatment. After they reached a height of 3−10 cm, depending on the
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Table 1. Bayer Codes, Scientific Names, and English Names
of the Tested Pest Plants
Table 2. Herbological Activities of Halogenated 2,2′-
Biphenols; Variation of R2
Bayer code
scientific name
English name
ABUTH
ALOMY
AVEFA
SETFA
Abutilon theophrasti
Alopecurus myosuroides
Avena fatua
velvetleaf
blackgrass
wild oat
Setaria faberi
giant foxtail
plant, they were treated with the active ingredients (6 mg), which had
been emulsified by addition of 2.4 mL of a 2:2:1 mixture of
cyclohexanone, DMSO, and Wethol EM31 (a nonionic emulsifier
produced by BASF SE, Ludwigshafen, Germany) and 1% DASH,
diluted with deionized water to the corresponding spray volume and
sprayed on the plants via a spray nozzle. DASH is a commercial
adjuvant produced by BASF, especially developed for use with acidic
agrochemicals. The mixture described above is frequently used as a
standard preparation in greenhouse experiments and does not have an
impact on the activity of the certain ingredient. The application rate
corresponds to 2 kg/ha with an application volume of 750 L/ha.
The plants were kept at 20−35 °C. The test period extended over
21 days. During this time, the plants were tended, and their response
to the individual treatments was visually evaluated. Evaluation was
carried out using a scale from 0−100: 100 means complete destruction
of at least the aerial moieties, and 0 means no damage or normal
course of growth. The last column in Tables 2−4 indicates the average
ratio of destruction over all applied species.
weeds in corn, as well as Alopecurus myosuroides (ALOMY) and
Avena fatua (AVEFA), key weeds in cereals, have been
selected.13
In contrast to the high activity toward weeds, no impact on
insects was observed. Upon application of the 2,2′-biphenol
samples at a dose rate of 2500 ppm on yellow fever mosquito
(Aedes aegypti), boll weevil (Anthonomus grandis), Mediterra-
nean fruit fly (Ceratitis capitata), tobacco budworm (Heliothis
virescens), green peach aphid (Myzus persicae), and vetch aphid
(Megoura viciae) no toxicity could be observed.
Whereas the pre-emergence impact of the fluorinated 2,2′-
biphenols is rather moderate and in most cases no germination
inhibition effect could be observed (results not shown), all of
the studied 2,2′-biphenols (4) exhibit strong postemergence
activity upon contact with the test plants (see Tables 2−5).
Looking closer at the emerged symptoms, one could observe a
rapid tissue necrosis that often appears when dealing with
nonsystemic contact herbicides caused by uncoupler activity
and ROS formation (reactive oxygen species).1
For 3,3′,5,5′-substituted 2,2′-biphenols the influence of a
varying substitution pattern is shown in Tables 2−4. When the
substituent in the para-position to the hydroxy group (R2) is
altered with R4 = F, the activity increases in the following order:
Cl > F > Me (see Table 2). When R4 is varied while
maintaining R2 = F, the activity significantly decreases in the
following order: Cl > F > Br (see Table 3). A comparison of
RESULTS AND DISCUSSION
■
Synthesis of the Tested Compounds. A reliable
procedure to prepare the highly fluorinated biphenols 4 was
developed in our laboratory (see Figure 1). An Ullmann-type
coupling reaction with activated copper powder yielding the
2,2′-bisanisoles 3 is followed by a deprotection with BBr3.12 As
starting material, the fluorinated iodoanisoles 2 are employed,
which are readily accessible by a telescoped iodination/
methylation sequence from commercially available fluorinated
phenols 1.11 The iodination of 1 is performed with an I2/I−
mixture under alkaline conditions. This sequence enables access
to a broad range of 2,2′-biphenol derivatives and tolerates
chloro, bromo, nitro, and methyl moieties.
Table 3. Herbological activities of Halogenated 2,2′-
Biphenols; Variation of R4
Biological Tests of 2,2′-Biphenols and 2,2′-Bisani-
soles. The test series was conducted in pre- and
postemergence with an application rate of 2 kg/ha. The results
of the herbicidal activity tests are summarized in Tables 2−5,
whereby 0 correlates with no damage to the test plant and 100
with total weed control. As test plants, Abutilon theophrasti
(ABUTH) and Setaria faberi (SETFA), representing two key
Figure 1. Preparation of halogenated 2,2′-bisanisoles and 2,2′-biphenols; R = Cl, Br, CH3.
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compounds which merely differ in the number and positions of
fluorine substituents shows that fluorine in positions R3 and R4
is required for high activity, whereas additional fluorine in
position R2 seems to lower the performance significantly (see
Table 4).
and Table 5). The molecular structure of partially O-methylated
4b was confirmed by X-ray analysis of a suitable single crystal
(see Figure 3).
Table 5. Influence of Partial and Full O-Derivatization on
the Herbological Activity of 2,2′-Biphenols; FG =
−CH2COOH, −CH2COOtBu
Table 4. Influence of the Substitution Pattern on the
Biological Activity of Fluorinated 2,2′-Biphenols
A comparison of the average herbicidal activity of
halogenated 2,2′-biphenols shows that Setaria faberi exhibits
the highest susceptibilities among the target plants with an
average biphenol activity of 88 (see Figure 2). Whereas the
Figure 3. Molecular structure of 5c obtained by X-ray analysis of a
single crystal.
Furthermore, the carboxymethyl group as a typical feature of
auxin-type herbicides14,15 such as 2,4-dichlorophenoxyacetic
acid (see Figure 4, right) was incorporated into the 2,2′-
Figure 2. Susceptibility of the test plants toward the studied 2,2′-
biphenols.
impact on Abutilon theophrasti is still in a moderate range
(average activity = 48). Avena fatua and Alopecurus myosuroides
exhibit rather poor susceptibilities (24 and 18). This general
trend can partly be explained by the sensitivity of the
considered species, as Avena fatua and Alopecurus myosuroides
(representing two very important key weeds in cereals) are
usually very hard to control in an effective manner. In contrast
to this, the intrinsic tolerance of the other species such as
Setaria faberi is significantly lower, and as a result, the total
vegetation control of the applied 2,2′-biphenols therefore is
remarkably higher.
Modification of the Structures. As the results of the
biological tests of halogenated 2,2′-biphenols appeared to be
very promising, further steps were taken to gain a better
understanding of the structure−activity relationship. Of
particular interest is the influence of the hydroxy functionality
on the activity of the studied compounds, as biological tests of
the halogenated 2,2′-bisanisoles 3 according to the described
procedure (Materials and Methods) revealed considerably
lower biological activities compared to the corresponding
2,2′-biphenols 4 (results not shown). To determine the active
site of the molecule, the partial modification of three active 2,2′-
biphenol species 4a, 4b, and 4c with a methyl group was
performed, leading to compounds 5a, 5b, and 5c (see Figure 1
Figure 4. Auxin-type substituted 2,2′-biphenols 6a, 6b, 7a, and 7b
(left) and 2,4-dichlorophenoxyacetic acid (2,4-D) (right).
biphenol structure, leading to 1- and 2-fold substituted
compounds 6a and 6b (see Figure 4, left and middle). This
modification was performed to explore the possibility of a
synergistic combination with auxin-type herbicidal property. 6a
and 6b were obtained by conversion of 2,2′-biphenol 4b with 2-
bromoacetic acid tert-butyl ester under basic conditions and
subsequent cleavage of ester 7a and 7b, respectively, with
trifluoroacetic acid (see Figure 5).
For the partially protected biphenols 5a, 5b, and 5c a
complete loss of weed control was observed (see Table 5). As
the methylation of a single as well as of both OH groups (2,2′-
bisanisoles 3) leads to significantly deteriorated activities, a
specific interaction between phenolic OH and active enzyme
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Figure 5. Preparation of auxin-type substituted 2,2′-biphenols 6a, 6b, 7a, and 7b.
sites in the plant metabolism is conceivable (e.g., hydrogen
bonding). Another explanation for the reduced performance of
the applied compounds together with the plants could also be
their ADME properties (the term ADME is an acronym in
pharmacokinetics and pharmacology for absorption, distribu-
tion, metabolism. and excretion, and in this case describes the
disposition of an agricultural compound within the plant
organism). By blocking the free hydroxy group with an alkyl
moiety, the acidity of the compound is reduced dramatically
and, therefore, the foliar uptake of the compound could also be
decreased. Similarly, partial and full O-functionalization with
the carboxymethyl group (compounds 6a and 6b) and the tert-
butyloxycarbonylmethyl group (compounds 7a and 7b) leads
to a full suppression of the performance. These results indicate
that the whole biphenol unit is crucial for herbicidal impact.
The applicability of 2,2′-biphenols 4 for crop protection was
studied, and high antipest plant activities were found in many
cases. A clear correlation between structural elements and
biological effect was found. The presence of hydroxy
functionalities significantly enhances the activity toward weeds
compared to methoxy groups. Specific interactions between
these hydroxy functionalities and active enzyme sites (e.g.,
hydrogen bonding) seem to play an important role in the mode
of action. Although the impact of these compounds is at an
interesting level for a lead structure, an improvement in
greenhouse activity by a factor of at least 10 will still be
required to approach commercially acceptable level. In addition
to that, one would also have to consider crop safety and
evaluate the tolerance of the applied compounds against target
crops such as wheat, corn, and rice, which was not performed
within our studies. Within the range of tested compounds, 3-
chloro-5-fluoro-2,2′-biphenol 4a is the candidate with the most
promising effectiveness. Among the target plants, Setaria faberi
exhibits the highest susceptibilities.
found that the combination of structural motifs from auxin-type
herbicides with the 2,2′-biphenol structure leads to a
suppression of the weed control instead of a synergistically
enhanced performance.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +49 6131 3926069. Fax: +49 6131 3926777. E-mail:
waldvogel@uni-mainz.de.
Present Address
#Department of Chemistry and Biochemistry, University of
CaliforniaSanta Barbara, Santa Barbara, CA 93106, United
States.
Funding
S.R.W. and R.F. are grateful for financial support by
Bundesministerium fur Bildung und Forschung (HE-Lion,
̈
03X4612J).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The collaboration with the Kompetenzzentrum der Integrierten
Naturstoff-Forschung (University of Mainz) is highly appre-
ciated.
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