Synthesis of 3,3-Dimethylbutanol and 3,3-Dimethylbutanal, Important Intermediates in the Synthesis of Neotame
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- Tanielyan, S.K. & Augustine, R.L. Top Catal (2012) 55: 625. doi:10.1007/s11244-012-9841-z
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It has been shown that some N-alkyl derivatives of Aspartame (1) are enhanced sweetening agents . In particular, the 3,3-dimethylbutyl derivative, 2, (Neotame) is about 70 times sweeter than Aspartame. With this in mind a research program directed toward the synthesis of 3,3-dimethylbutanal (3) was begun. The first phase of this research involved the synthesis of 3,3-dimethylbutanol (4) by the acid catalyzed alkylation of isobutene with ethylene to give the sulfate ester  which was readily hydrolyzed to the alcohol, 4, in isolated yields in the 70–75 % range. It was found that the most efficient method for the conversion of 4 to the aldehyde, 3, was by a vapor phase dehydrogenation over a copper catalyst. The effect which the reaction variables have on the production of 4 will be discussed. This will include factors such as the ethylene pressure, the acid/isobutene ratio, the use of a hydrocarbon solvent, the reaction temperature and the mode of addition of the isobutene. The discussion of the dehydrogenation procedure will include the nature of the catalyst used and the reaction parameters needed to maximize the formation of 3 and keeping the amount of the over-oxidation carboxylic acid product below 1 %.
KeywordsIsobutene condensationEthylene–alkene condensationAlkylsulfate hydrolysis3,3-Dimethylbutanol formationDimethylbutanol oxidationDimethylbutanol dehydrogenation
2 Results and Discussion
Reaction parameters, the ranges investigated and the “optimal” conditions used for the preparation of the alkyl sulfate
Slow, medium, high
214 mmol/20 mL heptane
Sulfuric acid quantity
428 mmol/30 mL heptane
Sulfuric acid/isobutene ratio
−5 to 25 °C
n-Alkanes, pentane, hexane, heptane, decane
The first reaction examined was a sodium hypochlorite oxidation catalyzed by TEMPO which was based on the procedure described by Anelli [3, 4]. The Anelli procedure, however, involved the use of large quantities of methylene chloride as a solvent and the use of KBr as a co-oxidant, two materials which are not environmentally acceptable. This procedure was modified with the substitution of sodium tetraborate (Borax) as the co-oxidant, elimination of the solvent altogether by running the reaction with the neat alcohol and minimizing the amount of bleach and buffer solutions used [5, 6]. The composition of the mixture at the end of the reaction was primarily a concentrated NaCl solution from which the product aldehyde, 3, was easily separated in 83–85 % yield. The aldehyde obtained by a phase separation on a commercial scale was sufficiently pure to be used in the production of Neotame by the N-alkylation of Aspartame.
At this point the catalyst was calcined at 400 °C for 1 h at 50 cc/min air flow and then reduced in a 50 cc/min stream of hydrogen for 1 h more. The resulting catalyst was used to investigate the effect of reaction temperature on the dehydrogenation with the results summarized in the TMP Region of Fig. 3. At 300 °C the conversion and productivity were even lower than those observed for the uncalcined catalyst. The by-product formation, though, was almost non-existent. Increasing the temperature resulted in a significant increase in the conversion and productivity of the reaction. It also promoted an increase in the amount of the by-products formed but the alkene increase was most significant. The amount of acid formed remained low.
The effect of changes in the argon flow rate (GFR region in Fig. 3) was investigated keeping the temperature at 330 °C and the alcohol flow at 0.05 cc/min. Higher gas flows resulted in lowering the conversion while with the lower gas flows alkene formation increased. Changes in the liquid flow rate (LFR region in Fig. 3) were studied at 340 °C and an argon flow rate of 90 cc/min. Increasing the LFR resulted in a slight decrease in conversion, a significant decrease in by-product formation and an increase in productivity. Interestingly, the reaction selectivity remained constantly high regardless of the reaction conditions used.
The aldehyde, 3,3-dimethylbutanal (3) required for the synthesis of Neotame was produced by the oxidation or dehydrogenation of 3,3-dimethylbutanol (4) which was formed by the acid catalyzed condensation of ethylene and isobutene and hydrolysis of the intermediate sulfate ester.