Isoxaflutole

Isoxaflutol
Names
IUPAC name
(5-cyclopropyl-1,2-oxazol-4-yl)-[2-methylsulfonyl-4-(trifluoromethyl)phenyl]methanone
Other names
  • RPA201772
Identifiers
3D model (JSmol)
8344543
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.114.433 Edit this at Wikidata
EC Number
  • 604-222-4
UNII
  • InChI=1S/C15H12F3NO4S/c1-24(21,22)12-6-9(15(16,17)18)4-5-10(12)13(20)11-7-19-23-14(11)8-2-3-8/h4-8H,2-3H2,1H3 checkY
    Key: OYIKARCXOQLFHF-UHFFFAOYSA-N checkY
  • CS(=O)(=O)C1=C(C=CC(=C1)C(F)(F)F)C(=O)C2=C(ON=C2)C3CC3
Properties[1]
C15H12F3NO4S
Molar mass 359.32 g·mol−1
Appearance Off-white or pale yellow solid
Density 1.59 g/cm3
Melting point 138 °C (280 °F; 411 K)
6.2 mg/L
log P 2.32
Hazards
GHS labelling:
GHS08: Health hazard GHS09: Environmental hazard
Warning
H361d, H410
P203, P273, P280, P318, P391, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Isoxaflutole is a selective herbicide used mainly in maize crops.[1] It inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD)[2] and is sold under brand names including Balance and Merlin. It was first marketed by Rhône-Poulenc in 1996.

History

In the mid-1980s, scientists at Stauffer Chemical Company published patents to benzoyl-substituted cyclohexanediones (triketones) which led to their product mesotrione.[3] This encouraged workers at Rhône-Poulenc to expand their own research into molecules with the same mode of action as these 4-hydroxyphenylpyruvate dioxygenase inhibitors. In doing so, they found that isoxaflutole had commercial potential as a propesticide of a biologically active diketonitrile that it was converted into within plants.[4] It was developed under the code number RPA201772.[5][6]

Synthesis

The isoxazole ring of the heterocycle product is formed when hydroxylamine reacts in ethanol with an intermediate which is made from an appropriately substituted diketone with triethyl orthoformate, using acetic anhydride as solvent.[7]

The crystal structure of isoxaflutole has been determined.[8] Within plants, it is converted to the diketonitrile shown, which is herbicidally active as an HPPD inhibitor.[2] The advantage of applying isoxafluole rather than the diketonitrile is that the former is more readily taken up into plants from a soil treatment.[5]

Usage

Isoxaflutole was first marketed by Rhône-Poulenc in 1996. It controls weeds which are important in crops including corn and sugarcane.[5][9][10] These include broad-leaved-weeds from Amaranthus, Datura stramonium and ragweed species and annual grass weeds of Alopecurus, Eriochloa and Panicum species.[11]

The herbicide is usually applied to the soil in which the crop is growing, before the emergence of the weeds.[1] In the US it is applied almost exclusively in corn with annual use in 2018 about 600,000 pounds (270,000 kg).[12] The compound is often formulated in combination with the herbicide safener, cyprosulfamide.[13] For example, in the EU the product that was evaluated by regulators was a suspension concentrate containing 240 g/L isoxaflutole and 240 g/L cyprosulfamide.[14]

Human safety

The LD50 of isoxaflutole is over 5000 mg/kg (rats, oral),[1] The European Food Safety Authority set an acceptable daily intake for it at 0.02 mg/kg bodyweight.[14] The Codex Alimentarius database maintained by the FAO lists the maximum residue limits for isozaflutole in various food products, most of which are set at its 0.01 mg/kg or 0.02 mg/kg limit of detection for the combination of the compound and its diketonitrile.[15]

Brands

Isoxaflutole is the ISO common name[16] for the active ingredient which is formulated into the branded product sold to end-users. The brand names in use for herbicides containing isoxaflutole include Balance, Cadu Star, Merlin and Spade.[1]

References

  1. ^ a b c d e Pesticide Properties Database. "Isoxaflutole". University of Hertfordshire.
  2. ^ a b Moran, GR (Jan 2005). "4-Hydroxyphenylpyruvate dioxygenase" (PDF). Archives of Biochemistry and Biophysics. 433 (1): 117–28. doi:10.1016/j.abb.2004.08.015. PMID 15581571. Archived from the original (PDF) on 2014-03-03.
  3. ^ Beaudegnies, Renaud; Edmunds, Andrew J.F.; Fraser, Torquil E.M.; et al. (2009). "Herbicidal 4-hydroxyphenylpyruvate dioxygenase inhibitors—A review of the triketone chemistry story from a Syngenta perspective". Bioorganic & Medicinal Chemistry. 17 (12): 4134–4152. doi:10.1016/j.bmc.2009.03.015. PMID 19349184.
  4. ^ Garcia, Isabelle; Job, Dominique; Matringe, Michel (2000). "Inhibition of p -Hydroxyphenylpyruvate Dioxygenase by the Diketonitrile of Isoxaflutole: A Case of Half-Site Reactivity". Biochemistry. 39 (25): 7501–7507. doi:10.1021/bi000135h. PMID 10858299.
  5. ^ a b c Pallett, Kenneth E.; Cramp, Susan M.; Little, Julian P.; Veerasekaran, Ponnan; Crudace, Amanda J.; Slater, Ashley E. (2001). "Isoxaflutole: The background to its discovery and the basis of its herbicidal properties". Pest Management Science. 57 (2): 133–142. doi:10.1002/1526-4998(200102)57:2<133::AID-PS276>3.0.CO;2-0. PMID 11455644.
  6. ^ Jhala, Amit J.; Kumar, Vipan; Yadav, Ramawatar; et al. (2023). "4-Hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides: Past, present, and future". Weed Technology. 37: 1–14. doi:10.1017/wet.2022.79.
  7. ^ EP patent 0527036, Cain, P.A.; Cramp, S.M. & Little, G.M. et al., "4-Benzoylisoxazole derivatives and their use as herbicides", issued 1996-11-06, assigned to Rhone Poulenc Agriculture Ltd. 
  8. ^ Schinke, Jascha; Gelbrich, Thomas; Griesser, Ulrich J. (2022). "Crystal structure, PIXEL calculations of intermolecular interaction energies and solid-state characterization of the herbicide isoxaflutole". Acta Crystallographica Section E. 78 (10): 979–983. Bibcode:2022AcCrE..78..979S. doi:10.1107/S2056989022008647. PMC 9535835. PMID 36250109.
  9. ^ Van Almsick, Andreas (2009). "New HPPD-Inhibitors – A Proven Mode of Action as a New Hope to Solve Current Weed Problems". Outlooks on Pest Management. 20: 27–30. doi:10.1564/20feb09.
  10. ^ Ndikuryayo, Ferdinand; Moosavi, Behrooz; Yang, Wen-Chao; Yang, Guang-Fu (2017). "4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals". Journal of Agricultural and Food Chemistry. 65 (39): 8523–8537. doi:10.1021/acs.jafc.7b03851. PMID 28903556.
  11. ^ Bayer Crop Science (2024). "Balance Flexx Herbicide". Retrieved 2024-05-19.
  12. ^ US Geological Survey (2024-02-26). "Pesticide Use Maps - Isoxaflutole". Retrieved 2024-05-19.
  13. ^ Ahrens, Hartmut; Lange, Gudrun; Müller, Thomas; Rosinger, Chris; Willms, Lothar; Van Almsick, Andreas (2013). "4-Hydroxyphenylpyruvate Dioxygenase Inhibitors in Combination with Safeners: Solutions for Modern and Sustainable Agriculture". Angewandte Chemie International Edition. 52 (36): 9388–9398. doi:10.1002/anie.201302365. PMID 23893910.
  14. ^ a b "Peer review of the pesticide risk assessment of the active substance isoxaflutole". EFSA Journal. 14 (2). 2016. doi:10.2903/j.efsa.2016.4416. ISSN 1831-4732.
  15. ^ FAO / WHO. "Isoxaflutole". Retrieved 2024-05-19.
  16. ^ "Compendium of Pesticide Common Names: Isoxaflutole". BCPC. Retrieved 2024-05-19.