725-89-3

Usage

Uses

Used in Pharmaceutical Industry:
3,5-Bis(trifluoromethyl)benzoic acid is used as a synthetic intermediate for the development of various pharmaceutical compounds. Its unique chemical properties, including the presence of trifluoromethyl groups, make it a valuable building block in the synthesis of drugs with specific therapeutic targets and improved pharmacokinetic profiles.
Used in Chemical Synthesis:
3,5-Bis(trifluoromethyl)benzoic acid is used as a key intermediate in the synthesis of various organic compounds, including agrochemicals, dyes, and specialty chemicals. Its reactivity and the presence of the trifluoromethyl groups allow for the formation of a wide range of products with diverse applications.
Used in Research and Development:
3,5-Bis(trifluoromethyl)benzoic acid is utilized in research and development settings to explore its potential applications and properties. As a major metabolite of 3,5-bis(trifluoromethyl)benzyl ethers, it provides valuable insights into the metabolic pathways and biotransformation processes of related compounds, which can be useful in the design of new drugs and chemical entities.

InChI:InChI=1/C9H4F6O2/c10-8(11,12)5-1-4(7(16)17)2-6(3-5)9(13,14)15/h1-3H,(H,16,17)/p-1

Synthetic route

carbon dioxide (124-38-9) + 3,6-bis(trifluoromethyl)bromobenzene (328-70-1) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With n-butyllithium In diethyl ether at -75℃;	94%
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With isopropylmagnesium chloride In tetrahydrofuran at -10℃; for 1h; Stage #2: carbon dioxide In tetrahydrofuran at -45℃; under 1034.3 Torr; for 1h;	94%
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; hexane at -78 - 20℃;	90.3%
(i) Mg, I2, Et2O, (ii) /BRN= 1900390/; Multistep reaction;

3,5-bis(trifluoromethyl)benzoyl fluoride (401-96-7) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With water In diethyl ether	85%

2-hydroxy-4-phenylbutanenitrile (121054-03-3) + 3,5-bis(trifluoromethyl)benzoic anhydride (155929-90-1) → 3,5-bistrifluoromethylbenzoic acid (725-89-3) + 1-cyano-3-phenylpropyl 3,5-bis(trifluoromethyl)benzoate

Conditions	Yield
Stage #1: 2-hydroxy-4-phenylbutanenitrile; 3,5-bis(trifluoromethyl)benzoic anhydride With triethylamine In dichloromethane at 20℃; for 2h; Stage #2: With hydrogenchloride In water	A n/a B 85%

1,3,5-tris(trifluoromethyl)benzene (729-81-7) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
Stage #1: 1,3,5-tris(trifluoromethyl)benzene With trifluorormethanesulfonic acid In chloroform for 4h; Inert atmosphere; Stage #2: With water In chloroform Inert atmosphere;	82%

3,5-bis(trifluoromethyl)styrene (349-59-7) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With methyl 3,5-bis((1H-1,2,4-triazol-1-yl)methyl)benzoate; oxygen; sodium acetate; nickel dibromide at 120℃; under 760.051 - 912.061 Torr; for 48h; chemoselective reaction;	80%

carbon monoxide (201230-82-2) + 3,5-bis(trifluoromethyl)iodobenzene (328-73-4) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With water; potassium carbonate In acetonitrile at 100℃; under 3750.38 Torr; for 0.0161111h;	79%

(2S,3S,5R,6R)-5-hydroxy-2-methoxy-4-oxo-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3-yl pivalate (90213-79-9) + 3,5-bis(trifluoromethyl)benzoic anhydride (155929-90-1) → 3,5-bistrifluoromethylbenzoic acid (725-89-3) + (2R,3R,5S,6S)-6-methoxy-4-oxo-5-(pivaloyloxy)-2-(pivaloyloxymethyl)tetrahydro-2H-pyran-3-yl 3,5-bis(trifluoromethyl)benzoate

Conditions	Yield
Stage #1: (2S,3S,5R,6R)-5-hydroxy-2-methoxy-4-oxo-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3-yl pivalate; 3,5-bis(trifluoromethyl)benzoic anhydride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: With hydrogenchloride In water	A n/a B 71.8%

carbon dioxide (124-38-9) + 1,3-bis(trifluoromethyl)benzene (402-31-3) → 2,4-bis(trifluoromethyl)benzoic acid (32890-87-2) + 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With N,N,N',N'',N'''-pentamethyldiethylenetriamine; sec.-butyllithium In tetrahydrofuran at -75℃; for 2h;	A 38% B 14%

3,5-bis(trifluoromethyl)benzoic anhydride (155929-90-1) + D-glucurono-3,6-lactone acetonide (3067-56-9, 20513-98-8, 25159-39-1, 26623-22-3, 29514-28-1, 85080-95-1) → 3,5-bistrifluoromethylbenzoic acid (725-89-3) + 1,2-O-isopropylidene-5-O-(3,5-bis(trifluoromethyl)benzoyl)-α-D-xylo-hexofuranurono-6,3-lactone

Conditions	Yield
Stage #1: 3,5-bis(trifluoromethyl)benzoic anhydride; D-glucurono-3,6-lactone acetonide With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: With hydrogenchloride In water	A n/a B 31.6%

carbon dioxide (124-38-9) + 1,3-bis(trifluoromethyl)benzene (402-31-3) → 2,6-bis(trifluoromethyl)benzoic acid (24821-22-5) + 2,4-bis(trifluoromethyl)benzoic acid (32890-87-2) + 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With 2,2,6,6-tetramethyl-piperidine; n-butyllithium 1.) THF, -78 deg C, 1.5 h, 2.) THF; Yield given; Multistep reaction. Yields of byproduct given;

1,3-bis(trifluoromethyl)benzene (402-31-3) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 94 percent / sulfuric acid; 1,3-dibromo-5,5-dimethylhydantoin / acetic acid / 4 h / 45 °C 2.1: i-PrMgCl / tetrahydrofuran / 1 h / -10 °C 2.2: 94 percent / tetrahydrofuran / 1 h / -45 °C / 1034.3 Torr View Scheme
Multi-step reaction with 2 steps 1: 87 percent / 96percent H2SO4, N,N'-dibromo-5,5-dimethylhydantoin / 24 h / 0 °C 2: 94 percent / BuLi / diethyl ether / -75 °C View Scheme
Multi-step reaction with 2 steps 2: (i) Mg, I2, Et2O, (ii) /BRN= 1900390/ View Scheme

4,4'-dimethoxybenzhydryl 3,5-bis(trifluoromethyl)benzoate → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
In ethanol; dichloromethane at 25℃; Kinetics;

3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride (785-56-8) → 3,5-bistrifluoromethylbenzoic acid (725-89-3) + 1-cyano-3-phenylpropyl 3,5-bis(trifluoromethyl)benzoate

Conditions	Yield
Multi-step reaction with 2 steps 1: phosphoric acid; acetic anhydride / 150 - 190 °C 2: triethylamine / dichloromethane / 2 h / 20 °C View Scheme

3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride (785-56-8) → 3,5-bistrifluoromethylbenzoic acid (725-89-3) + (2R,3R,5S,6S)-6-methoxy-4-oxo-5-(pivaloyloxy)-2-(pivaloyloxymethyl)tetrahydro-2H-pyran-3-yl 3,5-bis(trifluoromethyl)benzoate

Conditions	Yield
Multi-step reaction with 2 steps 1: phosphoric acid; acetic anhydride / 150 - 190 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C View Scheme

3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride (785-56-8) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: phosphoric acid; acetic anhydride / 150 - 190 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C View Scheme

carbon dioxide (124-38-9) + 1,3-bis(trifluoromethyl)benzene (402-31-3) → 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions

Yield

Stage #1: carbon dioxide; 1,3-bis(trifluoromethyl)benzene With [1,2-bis(dicyclohexylphosphino)ethane]rhodium(I) chloride dimer; Al(3+)*1.5CH3(1-)*1.5C2H5O(1-); tetramethylurea In N,N-dimethyl acetamide at 20 - 145℃; under 760.051 Torr; for 6h; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; N,N-dimethyl acetamide; water Catalytic behavior; Inert atmosphere; regioselective reaction;

3,5-bis(trifluoromethyl)benzenemethanol (32707-89-4) → 3,5-Bis(trifluoromethyl)benzaldehyde (401-95-6) + 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; laccase from Trametes versicolor; oxygen In water at 20℃; for 120h; Enzymatic reaction;	A 48 %Spectr. B 21 %Spectr.

(S)-Mandelic acid (17199-29-0) + diruthenium tetra(3,5-bis(trifluoromethyl)) benzoate → 3,5-bistrifluoromethylbenzoic acid (725-89-3) + diruthenium tetra (L-mandelate)

Conditions	Yield
at 55℃; for 2h; Kinetics; Equilibrium constant; Temperature;

diruthenium tetra(3,5-bis(trifluoromethyl)) benzoate + acetic acid (64-19-7) → tetra-μ-acetato-ruthenium(II) + 3,5-bistrifluoromethylbenzoic acid (725-89-3)

Conditions	Yield
at 55℃; for 2h; Kinetics; Equilibrium constant; Temperature;

Upstream product

• 124-38-9 carbon dioxide 
• 328-70-1 3,6-bis(trifluoromethyl)bromobenzene 
• 402-31-3 1,3-bis(trifluoromethyl)benzene 
• 401-96-7 3,5-bis(trifluoromethyl)benzoyl fluoride 
• 729-81-7 1,3,5-tris(trifluoromethyl)benzene 
• 121054-03-3 2-hydroxy-4-phenylbutanenitrile 
• 155929-90-1 3,5-bis(trifluoromethyl)benzoic anhydride 
• 90213-79-9 (2S,3S,5R,6R)-5-hydroxy-2-methoxy-4-oxo-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3-yl pivalate 
• 3067-56-9 D-glucurono-3,6-lactone acetonide 
• 785-56-8 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride 
• 349-59-7 3,5-bis(trifluoromethyl)styrene 
• 32707-89-4 3,5-bis(trifluoromethyl)benzenemethanol 
• 17199-29-0 (S)-Mandelic acid 
• 75462-61-2 3,5-bis(trifluoromethyl)benzylchloride 

Downstream Products

• 785-56-8 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride 
• 32707-89-4 3,5-bis(trifluoromethyl)benzenemethanol 
• 401-95-6 3,5-Bis(trifluoromethyl)benzaldehyde 
• 131805-94-2 2-bromo-1-[3,5-di(trifluoromethyl)phenyl]ethan-1-one 
• 380909-12-6 3-{4-[5-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-phenyl}-2-isopropoxy-propionic acid methyl ester 
• 380909-20-6 3-(4-{2-[5-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid methyl ester 
• 551943-85-2 3,5-Bis-trifluoromethyl-benzoic acid (S)-2-phenyl-2-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-ethyl ester 
• 551943-86-3 3,5-Bis-trifluoromethyl-benzoic acid (R)-2-phenyl-2-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-ethyl ester 
• 155929-90-1 3,5-bis(trifluoromethyl)benzoic anhydride 
• 26107-82-4 3,5-bis-(trifluoromethyl)benzoic acid hydrazide 
• 610799-00-3 N-(1-Boc-4-piperidinyl-benzylamino)-sulfonyl-3,5-bis-trifluoromethyl-benzamide 

Relevant academic research and scientific papers

Milled Dry Ice as a C1 Source for the Carboxylation of Aryl Halides

The use of carbon dioxide as a C1 chemical feedstock remains an active field of research. Here we showcase the use of milled dry ice as a method to promote the availability of CO 2in a reaction solution, permitting practical synthesis of arylcarboxylic acids. Notably, the use of milled dry ice produces marked increases in yields relative to those obtained with gaseous CO 2, as previously reported in the literature.

Ferric ion concentration-controlled aerobic photo-oxidation of benzylic C–H bond with high selectivity and conversion

A Fe(III)-promoted highly selective photo-oxidation of benzylic C–H bond delivering relative carbonyl products is reported. By altering the concentration of ferric salt, methylarenes can be selectively oxidized under UV irradiation to furnish aromatic aldehydes or acids, respectively. By this protocol, the oxidation of ethylarenes provides the corresponding acetophenones. The reaction is inferred to involve divergent pathways in different concentrations of catalyst for the alternative selectivity between aldehydes and aicds. The reusable catalyst, high conversion and selectivity make this oxidation a green and economic protocol for the synthesis of aromatic carbonyl compounds.

Scrutinizing ligand exchange reactions in the formation of the precious group metal-organic framework RuII,II-HKUST-1: The impact of diruthenium tetracarboxylate precursor and modulator choice

The precious group metal (PGM) analogues of the iconic metal-organic framework [Cu3(BTC)2] (HKUST-1; BTC = 1,3,5 benzenetricarboxylate) still represent a synthetic challenge, especially if targeting the univalent and ideally defect-free RuII,IIvariant. Herein we present a systematic study employing the controlled secondary building unit approach (CSA) by using a variety of diruthenium tetracarboxylate complexes [Ru2(RCO2)4] as precursors in the synthesis of univalent Ru-HKUST-1 samples. Carboxylate ligand exchange test reactions suggest the importance of a pKamatch between precursor ligand and BTC linker. For example,l-mandelate substituted precursors resulted in the most “perfect” samples of the investigated series with a fourfold increase in crystalline domain sizes compared to the established acetate route (according to PXRD and HR-TEM), high compositional purity (FT-IR, Raman, TGA and elemental analysis) and feature a so far unprecedentedly high BET surface area of 1789 m2g?1with the expected pore size distribution and total pore volume all similar to the ideal HKUST-1 parent structure.

Aqueous Flow Hydroxycarbonylation of Aryl Halides Catalyzed by an Amphiphilic Polymer-Supported Palladium-Diphenylphosphine Catalyst

An aqueous continuous-flow reaction system is developed for the palladium-catalyzed hydroxycarbonylation of aryl halides. Flow hydroxycarbonylation of aryl halides in aqueous solution proceeds efficiently in a flow reactor containing a palladium-diphenylphosphine complex immobilized on an amphiphilic polystyrene-poly(ethylene glycol) resin to give the corresponding benzoic acids in excellent yields.

An Aerobic Alternative to Oxidative Ozonolysis of Styrenes

A general, selective and extremely efficient procedure for the aerobic cleavage of aromatic alkenes is presented. TON values in the range 6,000,000-10,000,000 are obtained for this nickel-catalyzed reaction performed in polyethylene glycol 400 under 1 atm of molecular oxygen. Mono-, di-, tri- and tetrasubstituted styrene derivatives are oxidatively cleaved by this reproducible protocol, also suitable for larger scale (1.5 g) reactions. The presence of several functional groups (alkyl, alkoxy, halogen, trifluoromethyl) is tolerated in the substrates. The mechanistic proposal to explain the selective generation of carboxylic acids and ketones from aromatic alkenes involves the participation of the polyol solvent in the presented oxidative process.

Laccase-Mediator System for Alcohol Oxidation to Carbonyls or Carboxylic Acids: Toward a Sustainable Synthesis of Profens

By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.

Direct carboxylation of simple arenes with CO2 through a rhodium-catalyzed C-H bond activation

Direct carboxylation of simple arenes under atmospheric pressure of CO2 is achieved through a rhodium-catalyzed C-H bond activation without the assistance of a directing group. Various arenes such as benzene, toluene, xylene, electron-rich or electron-deficient benzene derivatives, and heteroaromatics are directly carboxylated with high TONs. This journal is

Visible light photoredox-catalyzed deoxygenation of alcohols

Carbon-oxygen single bonds are ubiquitous in natural products whereas efficient methods for their reductive defunctionalization are rare. In this work an environmentally benign protocol for the activation of carbon-oxygen single bonds of alcohols towards a reductive bond cleavage under visible light photocatalysis was developed. Alcohols were activated as 3,5-bis(trifluoromethyl)-substituted benzoates and irradiation with blue light in the presence of [Ir(ppy)2( dtb-bpy)](PF6 ) as visible light photocatalyst and Hünig's base as sacrificial electron donor in an acetonitrile/water mixture generally gave good to excellent yields of the desired defunctionalized compounds. Functional group tolerance is high but the protocol developed is limited to benzylic, α-carbonyl, and α-cyanoalcohols; with other alcohols a slow partial C-F bond reduction in the 3,5-bis(trifluoromethyl)benzoate moiety occurs.

Method for estimating SN1 rate constants: Solvolytic reactivity of benzoates

Nucleofugalities of pentafluorobenzoate (PFB) and 2,4,6-trifluorobenzoate (TFB) leaving groups have been derived from the solvolysis rate constants of X,Y-substituted benzhydryl PFBs and TFBs measured in a series of aqueous solvents, by applying the LFER equation: log k = sf(Ef + Nf). The heterolysis rate constants of dianisylmethyl PFB and TFB, and those determined for 10 more dianisylmethyl benzoates in aqueous ethanol, constitute a set of reference benzoates whose experimental ΔG ? have been correlated with the ΔH? (calculated by PCM quantum-chemical method) of the model epoxy ring formation. Because of the excellent correlation (r = 0.997), the method for calculating the nucleofugalities of substituted benzoate LGs have been established, ultimately providing a method for determination of the SN1 reactivity for any benzoate in a given solvent. Using the ΔG? vs ΔH? correlation, and taking sf based on similarity, the nucleofugality parameters for about 70 benzoates have been determined in 90%, 80%, and 70% aqueous ethanol. The calculated intrinsic barriers for substituted benzoate leaving groups show that substrates producing more stabilized LGs proceed over lower intrinsic barriers. Substituents on the phenyl ring affect the solvolysis rate of benzhydryl benzoates by both field and inductive effects.

Protolytic defluorination of trifluoromethyl-substituted arenes

A series of trifluoromethyl-substituted arenes were studied in their reactions with Bronsted superacids. The products from these reactions suggest the formation of reactive electrophiles, such as carbocations, acylium cations or equivalent electrophilic species. As such, Friedel-Crafts-type reactions occur between these species and arene nucleophiles. NMR studies were done, and the results suggest the formation of an acyl group from the trifluoromethyl groups in the superacid.