Electrochemical reductive amination
by Yu. D. Smirnov and A. P. Tomilov
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Translated from Zhurnal Organicheskoi Khimii, Vol. 28, No. 1, pp. 51-58, January, 1992. Original article submitted January 23, 1990.
Article originally scanned by Snidely Whiplash. OCR & Editing was done by Rhodium. HTMLized by MescalToad.
1. Amination of aliphatic ketones by primary amines
The reductive amination of aliphatic ketones in aqueous solutions of
primary amines was realized by an electrochemical method. The best yields
of the secondary amines were obtained at lead and cadmium cathodes in
an aqueous electrolytic solution at pH 11-12. Elongation and branching
One of the most accessible methods for the synthesis of primary and
secondary amines is reductive amination [1,2], which involves catalytic
hydrogenation of a mixture of a carbonyl compound with ammonia or a
primary amine. As a rule this reaction requires temperatures up to 150C
and pressures up to 150 atm, and its realization on a laboratory scale
therefore requires special equipment. In order to conduct the reaction
on more accessible laboratory equipment attempts were made to use other
As far back as the beginning of the present century a German patent was taken out on the production of methylamine by electrochemical reduction of a mixture of formaldehyde and ammonia . However, this method only began to attract the attention of researchers toward the end of the sixties. In  the production of amines by electrolysis of a ketone with an aqueous solution of ammonia at a spongy lead cathode was investigated. Amines were obtained from 2-butanone, 3-pentanone, and cyclohexanone with yields of 38, 34, and 28% respectively.
Rather more recently reductive amination of aliphatic ketones was realized
electrocatalytically at Raney nickel in an alkaline solution . The
aminating agent was ammonia. With vigorous agitation amines were obtained
from the respective ketones with the following yields (%): 2-Propanone
Comparatively recently electrochemical amination was used for the production of amino acids from the respective keto acids. Thus, 2-aminophenylacetic acid was obtained with an 88% yield from 2-keto-2-phenylacetic acid at a mercury cathode. Under the same conditions glutamic acid was obtained with a 42% yield and 2-aminobutyric acid with a 48% yield . Analogous reactions were also conducted at platinized platinum and palladium black cathodes .
Thus, researches conducted up to the present time have demonstrated the possibility of realizing the reductive amination of aliphatic and alicyclic ketones with ammonia as aminating agent. The possibility of using primary amines as aminating agents for the synthesis of secondary amines has been investigated very little.
In the work of Lund  it was shown that methylcyclohexylamine was
formed during the reduction of cyclohexanol in an aqueous solution of
methylamine acidified with hydrochloric acid at a mercury cathode, but
its yield was not indicated. In a buffer solution at pH 7 benzylideneaniline,
However, solutions of lithium chloride in methylamine have very low conductivity, and the method cannot be recommended for practical purposes. The aim of the present investigation was to develop a convenient preparative method for the synthesis of secondary amines starting from aliphatic ketones with the use of readily conducting aqueous solutions.
It is known that reductive amination takes place in two conjugate stages (1) and (2).
(1) R1R2C=O + R-NH2 <=> R1R2C=N-R + H2O
In addition to this main reaction, the side reduction of the ketone to a secondary alcohol (3) occurs during electrolysis, and hydrogen is released (4).
(3) R1R2C=O + 2e- + 2H+ => R1R2CHOH
Since reaction (1) is accelerated by acid-base catalysts, it was to be expected that the whole process would depend substantially on the pH of the medium. Initially the reductive amination process was studied for the amination of 2-butanone by methylamine with the aim of determining its principal relationships. As expected, the yield of the secondary amine depends substantially on the pH of the medium. In weakly acidic and weakly alkaline solutions (pH 5-9) the main electrolysis product is 2-butanol, the amount of which decreases gradually with increase in pH and reaches a minimum at pH 12. At the same time the amount of secondary amine formed increases with increase of the pH and reaches a maximum (60-70%) at pH 12. Further increase in the alkalinity leads to some reduction in the yield of the secondary amine and to an increase in the release of hydrogen. The most marked increase in the yield of the secondary amine starts at pH 10.
Further experiments showed that the yields of butanol and amine also depend on the amounts of primary amine and ketone taken for electrolysis but to a lesser degree than in the case of the pH value (Table 1).
TABLE 1. The Dependence of the Current Yield (%) of the Reduction Products on the Molar Ratio of the Ketone and Primary Amine
Note: The cathode was lead, 1N aqueous solution of potassium phosphate, pH 12, current density 0.0397 A/cm2, 18-20C, 0.35 mole of 2-butanone.
A small excess of the primary amine in relation to the ketone assists in the formation of the secondary amine and in reducing the yields of the alcohol and hydrogen. With the methylamine and 2-butanone in a ratio of 1.2:1 the yield of the secondary amine amounts to 64.5%. Departure from this ratio leads to a reduction in the yield of 2-methylaminobutane and to an increase in the current yield of hydrogen.
Apart from the above-mentioned factors the yield of the electrolysis products also depends on the cathode material (Table 2). The highest yields of the secondary amine (55-60% with respect to current) were obtained at metals with a high hydrogen overpotential (lead, cadmium, and zinc). At mercurized graphite and copper the yields were insignificant, while at tin and graphite reduction hardly occurred at all. The electrode material affects not only the yield of the secondary amine but also the selectivity of the process. At all the tested electrode materials (except tin) 2-butanol was formed in addition to the secondary amine. For the group of metals with a high hydrogen overpotential the highest yield of 2-butanol (15.1%) was observed at the zinc cathode, whereas the yield at cadmium did not exceed fractions of I %. The lowest selectivity for the production of the secondary amine was observed for the copper electrode, at which the yield of 2-butanol amounted to 29% with respect to current with a 10% yield of the secondary amine.
TABLE 2. The Current Yield (%) of the Reduction Products at Various Electrode Materials During the Amination of 2-Butanone with Methylamine
Note: 1% aqueous solution of potassium phosphate, pH 11, 20C, current density 0.0397 A/cm2, amount of amine 1.2 mole to 1 mole of ketone.
If the current density is increased, the yield of the secondary amine is reduced, while the yield of the 2-butanol and hydrogen is increased (Fig. 2). Thus, with a current density of 0.019 A/cm2 the secondary amine was obtained with a current yield of about 70.0%, whereas the yield when the current density was increased to 0.159 A/cm2 was 35.0%, i.e., an increase of eight times in the current density reduced the current yield of the secondary amine by half.
It was interesting to see how the yield of the secondary amine was
affected by change in the structure of the primary amine and the ketone.
In the series of methyl ketones (aminating agent methylamine) the amount
of the respective secondary amine formed decreased somewhat with increase
In contrast to the acyclic ketones, the alicyclic ketones readily form secondary amines during amination by methylainine with good current and material yields (50-70%). Somewhat unexpected results were obtained during the amination of cyclopentanone by cyclopentylamine; in this case the yield of the secondary amine amounted to only 24.8% with respect to current, although the general reduction process took place at a good rate and the current yield of hydrogen was not greater than 25-30%. In the case of the amination of 2-methylcyclopentanone the secondary amines were obtained as two stereoisomeric forms. The l-(N-methylamino)-2-methylcyclopentane formed during amination by methylamine contained 83.2% of the cis and 16.5% of the bans isomer. In the reaction with ethylamine the isomeric composition of the obtained secondary amine changes toward an increased amount of the bans form, the content of which in the mixture amounts to 28.3%.
In addition to the above-mentioned effects of the structure and the
size of the carbon radical of the carbonyl compounds on the yield of
the secondary amines, a similar relationship was observed during examination
of a series of amines. For almost all the ketones in the transition
from methylamine to
It should be noted that the overall reduction rate hardly decreases at all in the transition from lower to higher amines (as can be judged from the yield of hydrogen), but the amount of the respective alcohol increases significantly.
Like the monoamines, diamines can also be used as aminating agent. For example, during the amination of acetone by hexamethylenediamine we obtained a mixture of the mono- and dialkylated amine with an overall current yield of about 40%.
It is interesting to note that the alkylation of the mono-N-alkyl-substituted hexamethylenediamine by acetone takes place with significantly greater difficulty than that of free hexamethylenediamine.
The relationships we obtained on the effect of various factors on the reductive amination of ketones agree fully with the idea that the process takes place in two stages with previous chemical reaction, expressed by Eqs. (1) and (2). Thus, beginning at pH 10 the amount of amine formed increases sharply, while the amount of alcohol formed decreases at the same time, although the overall reduction rate (judged from the release of hydrogen) remains constant. The observed relationship is clearly due to the change in the concentration of the azomethine in the reaction medium in full agreement with the existing theories about the kinetics of the reactions of carbonyl compounds with bases, according to which the maximum rate is observed at a pH value equal to the pKa value of the base. Under these conditions, according to Eq. (1), half the amount of the primary amine is in the free state. Consequently, the concentration of the free form of the amine increases with increase in the pH value, and this in turn leads to an increase in the formation rate of the azomethine and, finally, to an increase in the yield of the secondary amine.
TABLE 3. The Current Yield (%) of the Products from Reduction of the Ketones in the Presence of Methylamine
Note: The cathode was lead, aquous solution of Potassium phosphate, pH 12, current density 0.0397 A/cm2, 18-20C, amine-ketone molar ratio 1.2:1.
TABLE 4. The Current Yield (%) of the Products from Reduction of the Ketones in the Presence of Ethylamine
Note: The cathode was lead, 1N potassium phosphate solution, pH 12, current density 0.0397 A/cm2, 18-20C.
The variation in the composition of the electrolysis products with increase in the current density is also due to the concentration of the azomethine, the formation rate of which at a certain value of the current density becomes the controlling stage in the formation of the secondary amine.
The difference in the formation rates of the azomethines is evidently
the main reason for the observed changes in the yields of the secondary
amines and the side products in the series of primary amines and ketones
with various structures. In this case, however, the occurrence of the
The best yields of the secondary amine were obtained for methyl ketones and lower amines, for which the formation rates of the azomethines under the electrolysis conditions were commensurable with their reduction rate or even somewhat exceeded it.
Increase in the length of the carbon chain and, particularly, its branching (both in the ketones and in the initial amines) lead to a significant reduction in the formation rate of the azomethine and, consequently, to a decrease in the yield of the secondary amine. In view of the fact that the rate of the electrode process depends largely on the rate of the preceding chemical reaction, however, the yield of the secondary amine with respect to current can be increased substantially by reducing the cathodic current density for compounds with low reactivity.