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22nd November 2011 @ 23:04
Paal-Knorr synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole from 2,5-hexanedione and 3,5-bis(trifluoromethyl)aniline.

Reaction Scheme

Reaction start time: 14:35 EST 23/11/2011
2,5-hexanedione (2.9 mL, 25 mmol, 1 equiv.) was added to 3,5-bis(trifluoromethyl)aniline (3.9 mL,25 mmol, 1 equiv.) and heated to 80 °C on an oil bath. TLC at 1 hr showed no reaction, and heat was increased to 120 °C. TLC at 3hr showed minor formation of product, and the reaction was left overnight at 120 °C. In the morning appearance was dark brown and TLC showed reaction not complete. TLC at 22 hr and 26 hr showed the reaction to be still incomplete, and it was left to continue overnight. TLC at 42 hr showed the reaction still incomplete, and development of a new impurity, and the reaction was removed from the heat. The dark brown mixture was extracted with ethyl acetate (20 mL) and washed with citric acid (10%, 20 ml, then 5%, 20 mL) and water (20 mL) followed by brine (20 mL), then dried over magnesium sulfate and filtered. The solution was then concentrated under reduced pressure. The resulting dark brown liquid (6.97 g, 91% of expected mass) was cooled on a brine ice bath but did not crystallize and NMR showed the presence of impurities. The liquid was purified by chromatography on silica (2% ethyl acetate in hexane) to give pure, impure and remainder fractions. The pure fraction was a pale yellow oil (2.67 g, 35%) which did not crystallize and the impure fraction formed a dark brown gum (2.62 g, 34%; remainder was 20%, mass balance 89%).

Data summary table:
Yield Melting point 1H NMR 13C NMR19F NMR IR Mass spec
1-1 (pure) 34% Liquid at room tempconsistent, suggests rotamers (pdf, all NMR .zip) consistent, fluorine quartets found (pdf, multiplets)(pdf)Yes (pdf, .dx) APCI 308 M+H (.pdf, .raw)


Comparison with literature:
The product is a known compound (CAS: 175205-51-3) but no experimental data were found.

High resolution mass spectrometry:
HRMS (APCI (+)) Calcd. for [C14H11F6NH+]: 306.0712, found: 306.0705.

NMR assignment:
1H NMR (CDCl3, 300 MHz): δ = 2.07 (d, (rotamers) 6H), 5.96 (d, (rotamers) J = 1.7 Hz, 2H), 7.72 (d (rotamers), J = 0.3Hz, 2H). 13C NMR (CDCl3, 300 MHz): δ = 13.1 (2C), 107.6 (2C), 121.5 (dq, J = 3.5, 3.8 Hz, 1C), 123.1 (q, J = 272.6, 2C), 128.6 (q, J = 3.6 Hz, 2C), 128.8 (2C), 133.0 (q, J = 33.9 Hz, 2C), 140.9 (2C).

Conclusions:
The impure fraction was used unsuccessfully in a Vilsmeier-Haack reaction (ZYH 4-1), resulting in a mixture of products. Vilsmeier-Haack reaction of the pure fraction was successful (ZYH 4-2, ZYH 4-3). Some small additional peaks in the NMR spectra suggest the product is not completely pure, and the oil became darker over time. Remaining pure fraction was stored in the freezer.

Method taken from:
Scale-up (100 mmol) of Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-6)

Product taken forward to:
Synthesis of 3,5-bis(trifluoromethyl) arylpyrrole based near neighbour analogue (ZYH 7-2)

TLC (10% EtOAc/petrol) visualised with UV and Vanillin:
TLC at 3 hr
TLC at 26 hr
TLC after washes

Spots from left to right: aniline; aniline and reaction mixture; reaction mixture; hexanedione and reaction mixture; hexanedione.
TLCs from chromatography test tubes (10% EtOAc/petrol) visualised with UV and Vanillin:
Chomatography TLC1
Chromatography TLC2


Risk and hazard assessment:
Risk assessment
Linked Posts
Attached Files
Risk assessment
reaction scheme
TLC at 1 hr
TLC at 3 hr
TLC at 18 hr
TLC at 22 hr
TLC at 26 hr
TLC at 42 hr
TLC after washes
raw data
1H NMR
TLC after washes
Chomatography TLC1
Chromatography TLC2
Pure fraction 1H NMR
Pure fraction 13C NMR
Pure fraction raw data
Impure fraction raw data
19F NMR
IR spectrum
19F NMR
all NMR data
MS pdf
MS data
IR data
13C NMR revised
13C NMR with multiplets
Comments
Re: Preparation of 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole (ZYH 1-1) by Paul Ylioja
23rd November 2011 @ 04:24
Reaction risk assessment approved verbally prior to reaction. Reaction carried out with supervision.
Re: Preparation of 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole (ZYH 1-1) by Matthew Todd
23rd November 2011 @ 05:53
Nice. Should be an interesting addition to the set, having those CF3 groups there.