Comparison of three methods for the methylation of aliphatic and aromatic compounds

Methylation protocols commonly call for acidic, hot conditions that are known to promote organic ¹ H/² H exchange in aromatic and aliphatic C-H bonds. Here we tested two such commonly used methods and compared a third that avoids these acidic conditions, to quantify isotope effects with each method and to directly determine acidic-exchange rates relevant to experimental conditions.

We compared acidic and non-acidic methylation approaches catalyzed by hydrochloric acid, acetyl chloride and EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)/DMAP (4-dimethylaminopyridine), respectively. These were applied to two analytes: phthalic acid (an aromatic) and octacosanoic acid (an aliphatic). We analyzed yield by gas chromatography/flame ionization (GC/FID) and hydrogen and carbon isotopic compositions by isotope ratio mass spectrometry (GC/IRMS). We quantified the ¹ H/² H exchange rate on dimethyl phthalate under acidic conditions with proton nuclear magnetic resonance (¹ H-NMR) measurements.

The δ² H and δ¹³ C values and yield were equivalent among the three methods for methyl octacosanoate. The two acidic methods resulted in comparable yield and isotopic composition of dimethyl phthalate; however, the non-acidic method resulted in lower δ² H and δ¹³ C values perhaps due to low yields. Concerns over acid-catalyzed ¹ H/² H exchange are unwarranted as the effect was trivial over a 12-h reaction time.

We find product isolation yield and evaporation to be the main concerns in the accurate determination of isotopic composition. ¹ H/² H exchange reactions are too slow to cause measurable isotope fractionation over the typical duration and reaction conditions used in methylation. Thus, we are able to recommend continued use of acidic catalysts in such methylation reactions for both aliphatic and aromatic compounds.