Investigation of Acid-Catalyzed Enolization of Acetophenones

Olivia Golebiewski, Dr. Nanette Wachter

Chemistry Department, Hofstra University, Hempstead-NY, 11550, USA

α-Carbon peak integrations of 4-substituted acetophenones in Acetic acid-d4 α-Carbon peak integrations of 4substituted acetophenones in MeOD-d4 α-Carbon peak integrations of 4-bromoacetophenone in MeOD-d4 at different temperatures

1.51 x 10-2

2.32 x 10-2

1.62 x 10-2

1.64 x 10-2

1.35 x 10 -2

1.48 x 10-2

H/D Coupling observed in 4-bromoacetophenone kinetics 1H-NMR

Kinetics 1H-NMR of DCl catalyzed enolization of 4-bromoacetophenone in methanol-d4

Results

The D/H exchange was observed by the decay of the αcarbon peak and the simultaneous growth of the solvent peak as it is enriched in hydrogen For both the acetic acidd4 and methanol-d4 solvent, the rates of D/H exchange by acid-catalyzed enolization were generally slower for acetophenones with electron-withdrawing substituents Whereas that rates of D/H exchange for acetophenones with electron-donating substituents were generally faster

As the temperature of the enolization reaction was increased the rate of D/H exchange also increased for 4bromoacetophenone in methanol-d4 The D/H exchange rates were lower for the methanol-d4 solvent due to solvent leveling

Conclusion and Next Steps

Methods

The acid-catalyzed enolization reactions of several 4-substituted acetophenones were monitored by NMR Spectroscopy 400MHz) Acetophenones (1mM) were prepared in 1 0mL of MeOD-d4 or acetic acid-d4 and with a catalytic amount of DCl (20μL) The receiver gain was established by a 1H-NMR experiment The kinetic 1H-NMR experiment was set up to perform a total of twenty-four scans over a two-hour period, every five minutes The experiments were performed at 20 30 and 40℃ The spectra were processed using DELTA NMR processing software The α-carbon peak (~2 5ppm) was integrated and normalized against the aromatic hydrogen peak (~7 9ppm) The relative D/H exchange rates were calculated 2

The D/H exchange rates are faster for the para-substituted acetophenones with electron donating groups because these groups (e g –OCH3) make the carbonyl more basic The protonation of the carbonyl of an acetophenone with an electron donating group allows for the formation of additional resonance structures The enol form and subsequently α-carbon nitration is more likely to occur Para-substituted acetophenones with electron withdrawing groups do not form any additional resonance structures and enol formation is less favorable as reflected by the slower D/H exchange rates Since furoxan formation was observed in methoxyacetophenones at high temperatures, the acid-catalyzed enolization of 4-methoxyactophenone should be studied by kinetic 1H-NMR at different temperatures as was performed with 4-bromoacetophenone 1 A kinetic 1H-NMR experiment of 4hydroxyacetophenone may also shed light on its tendency to undergo ring nitration

1) Nirode, W F.; Luis, J M.; Wicker, J F.; Wachter, N M Bioorg Med Chem Lett 2006 16, 2299-2301

2) Wachter, N M.; Tarbox H E Am Chem Soc 2021 1376, 137-148