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Aclonifen

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Aclonifen
Names
IUPAC name
2-chloro-6-nitro-3-phenoxyaniline
Other names
RPA099795
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.070.619 Edit this at Wikidata
EC Number
  • 277-704-1
UNII
  • InChI=1S/C12H9ClN2O3/c13-11-10(18-8-4-2-1-3-5-8)7-6-9(12(11)14)15(16)17/h1-7H,14H2 checkY
    Key: DDBMQDADIHOWIC-UHFFFAOYSA-N checkY
  • C1=CC=C(C=C1)OC2=C(C(=C(C=C2)[N+](=O)[O-])N)Cl
Properties[1]
C12H9ClN2O3
Molar mass 264.67 g·mol−1
Density 1.46 g/cm3
Melting point 81.2 °C (178.2 °F; 354.3 K)
1.4 mg/L (20 °C)
log P 4.37
Acidity (pKa) -3.15
Pharmacology
Legal status
  • AU: S6 (Poison)
Hazards
GHS labelling:[2]
GHS07: Exclamation markGHS08: Health hazardGHS09: Environmental hazard
Warning
H317, H351, H410
P201, P202, P261, P272, P273, P280, P281, P302+P352, P308+P313, P321, P333+P313, P363, P391, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Aclonifen is a diphenyl ether herbicide which has been used in agriculture since the 1980s. Its mode of action has been uncertain, with evidence suggesting it might interfere with carotenoid biosynthesis or inhibit the enzyme protoporphyrinogen oxidase (PPO). Both mechanisms could result in the observed whole-plant effect of bleaching (removal of leaf colour) and the compound includes chemical features (a nitro group attached to a diphenyl ether) that are known to result in PPO effects, as seen with acifluorfen, for example.[1][3][4] In 2020, further research revealed that aclonifen has a different and novel mode of action, targeting solanesyl diphosphate synthase which would also cause bleaching.[5][6]

History

The nitrophenyl ethers are a well-known class of herbicides, the oldest member of which was nitrofen, invented by Rohm & Haas and first registered for sale in 1964.[7] This area of chemistry became very competitive, with the Mobil Oil Corporation's filing in 1969 and grant in 1974 of a patent to the structural analog with a COOCH3 group adjacent to the nitro group of nitrofen.[8] This product, bifenox, was launched in 1981. Meanwhile, Rohm & Haas introduced acifluorfen (as its sodium salt) in 1980.[9] It had much improved properties including a wider spectrum of herbicidal effect and good safety to soybean crops. The first patent for this material was published in December 1975,[10]

  • Nitrofen
    Nitrofen
  • Bifenox
    Bifenox
  • Acifluorfen
    Acifluorfen

Celamerck scientists were also working on analogs retaining the 4-nitrodiphenyl ether framework and in 1978 filed a patent of relatively narrow scope which claimed compounds having an amine group adjacent to the nitro substituent and also having an additional chlorine atom between the amine and the oxygen of the diphenyl ether. 2-Chloro-3-phenoxy-6-nitroaniline was described as having selectivity, so that important grass weeds could be controlled within dicot crops and this lack of damage to the crop extended to some cereals.[11] Aclonifen was subsequently developed and marketed by Rhône-Poulenc under the code number RPA099795 and launched in 1983 in Europe.[1][12]

Synthesis

The synthesis of aclonifen

The preparation of aclonifen first described in Celamerck patents starts from 2,3,4-trichloronitrobenzene. This is reacted in an autoclave with ammonia in dimethyl sulfoxide. The intermediate aniline is treated with potassium phenolate in an Ullmann ether synthesis using acetonitrile as solvent.[11]

Mechanism of action

The detailed mechanism of action for nitro diphenyl ether herbicides such as acifluorfen was unknown at the time they were invented. The effects visible on whole plants are chlorosis and desiccation: in 1983 several hypotheses were advanced regarding the molecular-level interactions which might explain these symptoms.[13] By 1992, it was becoming clear that most compounds of this class inhibit the enzyme protoporphyrinogen oxidase (PPO), which leads to an accumulation of protoporphyrin IX in the plant cells. This is a potent photosensitizer which activates oxygen, leading to lipid peroxidation. Both light and oxygen are required for this process to kill the plant.[14][15][16]

Aclonifen was shown to be an inhibitor of PPO but in addition had effects on carotenoid synthesis, by inhibition of phytoene desaturase at similar concentrations in vitro.[3] This led to the conclusion that it expressed a dual mode of action.[4][17] In 2020, further research revealed that it is likely to have a completely different and novel mode of action, targeting solanesyl diphosphate synthase.[5] This has led to its being classified in its own group for the purposes of resistance management.[18]

Uses

Aclonifen is registered for use in the European Union, where a two-tiered approach is used for approval and authorisation. Before a formulated product can be developed for market, the active substance must be approved. Then authorisation for the specific product must be sought from every Member State that the applicant wants to sell it to. Afterwards, there is a monitoring programme to make sure the pesticide residues in food are below the limits set by the European Food Safety Authority. The active ingredient is registered for use against weeds in crops including cereals, potato and sunflower.[1][19] It is particularly safe to sunflower, owing to the metabolism which occurs in that crop.[20][21]

Aclonifen is now supplied by Bayer Crop Science under a variety of brand names according to the crop and formulation. For example, Proclus is used in winter wheat and Emerger in potatoes. It is normally applied pre-emergence (before weeds are visible in the crop) and controls or suppresses species including Alopecurus myosuroides, Anthemis cotula, Chenopodium album, Fallopia convolvulus, Galium aparine and Viola arvensis when used at application rates of 600 g a.i. per hectare.[22][23]

In the UK, following the withdrawal of linuron in 2017, aclonifen began to be used as a pre-emergence herbicide in potatoes.[24]

References

  1. ^ a b c d Pesticide Properties Database. "Aclonifen". University of Hertfordshire.
  2. ^ PubChem Database. "Aclonifen".
  3. ^ a b Kılınç, Özgür; Reynaud, Stéphane; Perez, Laurent; Tissut, Michel; Ravanel, Patrick (February 2009). "Physiological and biochemical modes of action of the diphenylether aclonifen". Pesticide Biochemistry and Physiology. 93 (2): 65–71. doi:10.1016/j.pestbp.2008.11.008.
  4. ^ a b Dayan, Franck E; Owens, Daniel K; Duke, Stephen O (2012-01-09). "Rationale for a natural products approach to herbicide discovery". Pest Management Science. 68 (4). Society of Chemical Industry (Wiley): 519–528. doi:10.1002/ps.2332. ISSN 1526-498X. PMID 22232033. S2CID 10841777.
  5. ^ a b Kahlau, Sabine; Schröder, Florian; Freigang, Jörg; Laber, Bernd; Lange, Gudrun; Passon, Daniel; Kleeßen, Sabrina; Lohse, Marc; Schulz, Arno; von Koskull-Döring, Pascal; Klie, Sebastian; Gille, Sascha (October 2020). "Aclonifen targets solanesyl diphosphate synthase, representing a novel mode of action for herbicides". Pest Management Science. 76 (10): 3377–3388. doi:10.1002/ps.5781. PMID 32034864. S2CID 211063448.
  6. ^ Pinho, Bárbara (2021-04-06). "The growing problem of pesticide resistance". Chemistry World.
  7. ^ Pesticide Properties Database. "Nitrofen". University of Hertfordshire. Retrieved 2021-03-03.
  8. ^ US patent 3784635, Theissen R.J., "Herbicidal 4-trifluoromethyl-4'-nitrodiphenyl ethers", issued 1974-01-08, assigned to Mobil Oil Corporation 
  9. ^ Pesticide Properties Database. "Acifluorfen-sodium". University of Hertfordshire. Retrieved 2021-03-03.
  10. ^ US patent 3928416, Bayer H. O.; Swithenbank C. & Yih R. Y., "Herbicidal 4-trifluoromethyl-4'-nitrodiphenyl ethers", issued 1975-12-23, assigned to Rohm & Haas 
  11. ^ a b US patent 4394159, Buck W.; Linden G. & Lust S. et al., "2-Chloro-3-(phenoxy or phenylthio)-6-6-nitro-anilines", issued 1981-09-16, assigned to Celamerck GmbH and Co KG 
  12. ^ Matringe, M.; Clair, D.; Scalla, R. (1990). "Effects of peroxidizing herbicides on protoporphyrin IX levels in non-chlorophyllous soybean cell culture". Pesticide Biochemistry and Physiology. 36 (3): 300–307. doi:10.1016/0048-3575(90)90039-5.
  13. ^ Ridley, Stuart M. (1983). "Interaction of Chloroplasts with Inhibitors". Plant Physiology. 72 (2): 461–468. doi:10.1104/pp.72.2.461. PMC 1066256. PMID 16663025.
  14. ^ Nandihalli, Ujjana B.; Duke, Mary V.; Duke, Stephen O. (1992). "Quantitative structure-activity relationships of protoporphyrinogen oxidase-inhibiting diphenyl ether herbicides". Pesticide Biochemistry and Physiology. 43 (3): 193–211. doi:10.1016/0048-3575(92)90033-V.
  15. ^ Dayan, Franck E.; Reddy, Krishna N.; Duke, Stephen O. (1999). "Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. pp. 141–161. doi:10.1007/978-3-642-58633-0_5. ISBN 978-3-642-63674-5.
  16. ^ Nagano, Eiki (1999). "Herbicidal Efficacy of Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. pp. 293–302. doi:10.1007/978-3-642-58633-0_11. ISBN 978-3-642-63674-5.
  17. ^ Kılınç, Özgür Kıvılcım (2015). "The Symptoms of Herbicidal Action: The Case of Aclonifen". Turkish Journal of Agriculture - Food Science and Technology. 3 (6): 472. doi:10.24925/turjaf.v3i6.472-477.391.
  18. ^ Weed Science Society of America (April 2021). "HRAC Mode of Action Updates" (PDF). wssa.net. Retrieved 2021-05-10.
  19. ^ "Conclusion regarding the peer review of the pesticide risk assessment of the active substance aclonifen". EFSA Journal. 6 (10). 2008. doi:10.2903/j.efsa.2008.149r.
  20. ^ Kılınç, Özgür; Grasset, Renaud; Reynaud, Stéphane (June 2011). "The herbicide aclonifen: The complex theoretical bases of sunflower tolerance". Pesticide Biochemistry and Physiology. 100 (2): 193–198. doi:10.1016/j.pestbp.2011.04.001.
  21. ^ Jursík, M.; Soukup, J.; Holec, J.; Andr, J.; Hamouzová, K. (2016). "Efficacy and selectivity of pre-emergent sunflower herbicides under different soil moisture conditions". Plant Protection Science. 51 (4): 214–222. doi:10.17221/82/2014-PPS.
  22. ^ "Proclus". cropscience.bayer.co.uk. 2020. Retrieved 2021-05-10.
  23. ^ "Emerger". cropscience.bayer.co.uk. 2019. Retrieved 2021-05-10.
  24. ^ Cunningham, Charlotte (12 April 2019). "New herbicide to help replace linuron". Crop Production Magazine. Retrieved 3 May 2021.
  • Aclonifen in the Pesticide Properties DataBase (PPDB)
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