Difluoroacetic Anhydride

• Catalog: OFC401672
• CAS: 401-67-2
• Category: Difluoromethylation Agents
• Synonyms: 2,2-Difluoroacetic anhydride
• Purity: >98.0%(GC)
• MDL Number: MFCD02093315

• IUPAC Name: (2,2-difluoroacetyl) 2,2-difluoroacetate
• InChI: InChI=1S/C4H2F4O3/c5-1(6)3(9)11-4(10)2(7)8/h1-2H
• InChI Key: IYXUFOCLMOXQSL-UHFFFAOYSA-N
• Isomeric SMILES: C(C(=O)OC(=O)C(F)F)(F)F
• EC Number: 674-863-2
• Reaxys Registry Number: 1783303

• Molecular Formula: C4H2F4O3
• Molecular Weight: 174.05
• Boiling Point: 127 °C
• Flash Point: 11 °C
• Specific Gravity: 1.60
• Refractive Index: 1.34
• Appearance: Colorless to light yellow to light orange clear liquid
• Storage: Store under inert gas
• Stability: Moisture sensitive

• XLogP3-AA: 1.6
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 4
• Exact Mass: 173.99400657 g/mol
• Monoisotopic Mass: 173.99400657 g/mol
• Topological Polar Surface Area: 43.4Ų
• Heavy Atom Count: 11
• Formal Charge: 0
• Complexity: 149

• HS Number: 2915.90.5050

Case Study

Visible-Light-Induced Hydrodifluoromethylation for the Application of Difluoroacetic Anhydride in Alkene Functionalization

Zhu X, et al. The Journal of Organic Chemistry, 2024, 89(12), 8828-8835.

Difluoroacetic anhydride was effectively utilized as a difluoromethyl radical precursor in a visible-light-induced hydrodifluoromethylation protocol targeting unactivated alkenes. This transformation was achieved through the synergistic action of photocatalysis and N-hydroxyphthalimide (NHPI) activation. Under visible-light irradiation, a photocatalyst facilitated the generation of a reactive difluoromethyl radical from difluoroacetic anhydride, which subsequently underwent regioselective addition to various alkenes. NHPI not only activated the anhydride via acyloxy radical formation but also played a dual role as a hydrogen atom donor in the final step of the radical chain mechanism. The method demonstrated broad substrate scope, with over 50 structurally diverse alkenes-including biologically relevant and drug-derived molecules-successfully converted under mild reaction conditions.

Difluoroacetic Anhydride for the Photochemical Difluoromethylation of Quinoxalin-2(1H)-ones

Zhang Y, et al. The Journal of Organic Chemistry, 2024, 89(2), 1199-1208.

Difluoroacetic anhydride was employed as a key reagent in the development of a novel, catalyst-free photochemical difluoromethylation protocol targeting quinoxalin-2(1H)-ones. In this method, quinoxalin-2(1H)-one substrates were subjected to visible-light irradiation in the presence of difluoroacetic anhydride and pyridine N-oxide under mild conditions. Notably, no external photocatalyst or metal additive was required. The reaction was conducted in acetonitrile at room temperature under blue LED light, allowing for efficient C3-selective difluoromethylation. Difluoroacetic anhydride served as the difluoromethyl source, undergoing activation via interaction with pyridine N-oxide under photochemical conditions to generate reactive difluoromethyl radicals. These radicals subsequently engaged the electron-rich C3-position of quinoxalin-2(1H)-ones, forming the desired C-CF₂H bond.

Difluoroacetic Anhydride for the Catalytic Difluoromethylation of Alkenes via In Situ Generated Bis(difluoroacetyl) Peroxide

Tagami T, et al. Advanced Synthesis and Catalysis, 2023, 365(21), 637-3647.

In this study, difluoroacetic anhydride (DFAA) was employed as a versatile CF₂H radical precursor for the copper-catalyzed difluoromethylation of alkenes under thermal conditions. The experimental protocol involved the in situ generation of bis(difluoroacetyl) peroxide (BDFAP) by reacting DFAA with aqueous hydrogen peroxide. This thermally labile peroxide served as the key radical initiator, enabling efficient amino-, allylic-, and oxy-difluoromethylation reactions without requiring photochemical activation. Remarkably, carbo-difluoromethylation was also achieved in the absence of a catalyst, underscoring the strong intrinsic reactivity of BDFAP. The methodology allowed for broad substrate scope and provided direct access to structurally diverse difluoromethylated compounds with potential applications in medicinal and agrochemical chemistry.

Difluoroacetic Anhydride for the Synthesis of 3-(Difluoromethyl)-1H-1,2,4-triazol-5(4H)-ones via Cyclization of Hydrazinecarboxamides

You Y, et al. Organic & Biomolecular Chemistry, 2019, 17(42), 9343-9347.

Difluoroacetic anhydride (DFAA) has been effectively employed as a key reagent in the synthesis of 3-(difluoromethyl)-1H-1,2,4-triazol-5(4H)-ones through the cyclization of aryl-substituted hydrazinecarboxamides. In this method, the reaction is carried out under mild conditions using DMF as solvent at 30 °C for 6 hours, enabling high functional group tolerance and achieving up to 97% yield across 43 substrate examples. Mechanistically, the transformation proceeds through a tandem process involving initial difluoroacetylation of the hydrazinecarboxamide, followed by intramolecular nucleophilic attack and subsequent water elimination to construct the triazolone core.The reaction demonstrates significant synthetic utility by incorporating difluoromethyl groups into heterocyclic frameworks, thereby enhancing the physicochemical properties of the resulting compounds.