
                    ELECTROCHEMICAL REDUCTIVE AMINATION
            1. AMINATION OF ALIPHATIC KETONES BY PRIMARY AMINES
                    by Yu. D. Smirnov and A. P. Tomilov

Translated from Zhurnal Organicheskoi Khimii, Vol. 28, No. 1, pp. 51-58,
January, 1992. Original article submitted January 23, 1990.

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 in the
carbon chain of the radicals both of the ketone and of the primary amine
lead to a reduction in the yield of the secondary amine. The yield of the
secondary amine is mainly determined by the rate of the chemical reaction
leading to the formation of the azomethine compound. preceding the
electrochemical reduction stage.

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 150_C 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
reducing agents. Attempts to conduct the reaction electrochemically have
taken a special position among these researches.

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 [3]. However, this method only began
to attract the attention of researchers toward the end of the sixties. In
[4] 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 [5]. The
aminating agent was ammonia. With vigorous agitation amines were obtained
from the respective ketones with the following yields (%): 2-Propanone
(78), 2-butanone (74), cyclohexanone (68), 3- pentanone (62), 2-pentanone
(57), 2-hexanone (37), 4-methyl-2-pentanone (34), 2-heptanone (23),
2-octanone (21).

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 [6]. Analogous
reactions were also conducted at platinized platinum and palladium black
cathodes [7].

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 [8] 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, produced by
the condensation of aniline and benzylideneaniline, produced by the
condensation of aniline and benzaldehyde, was reduced at a mercury cathode
to the corresponding amine with almost quantitative yield [9]. If the
aliphatic ketone is dissolved in anhydrous methylamine containing lithium
chloride as supporting electrolyte and the obtained mixture is submitted to
hydrolysis after 6 h, N-methylalkylamines are formed with yields amounting
to 73% for 2-heptanone, 70% for cyclohexanone, 70% for cyclopentanone, and
52% for diethyl ketone [10].

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
(2)	R1R2C=N-R + 2e- + 2H+ => R1R2CHNHR

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
(4)	2H+ + 2e- => H2

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

--------------------------------------------------------------------------
  Amine to       Amine
ketone ratio   conc. (M)     Sec. Amine         Alcohol         Hydrogen
--------------------------------------------------------------------------
     0.8          1.40          33.5             5.73             59.0
     1.0          1.75          60.8             4.65             29.7
     1.2          2.10          64.5             0.218            20.5
     1.5          2.62          49.7             0.112            27.2
--------------------------------------------------------------------------

Note: The cathode was lead, 1N aqueous solution of potassium phosphate,
      pH 12, current density 0.0397 A/cm2, 18-20øC, 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

--------------------------------------------------------------------------
        Electrode       Secondary
        material          Amine         Alcohol         Hydrogen
--------------------------------------------------------------------------
        Lead               60.8           1.9             20.5
        Cadmium            55.5          Traces           34.0
        Zinc               56.3           15.1            13.65
        Copper             10.0           29.5            58.0
        Tin                 -              -              100.0
        Graphite            -             1.52            95.0
        Mercurized
        Graphite           29.5           0.8             51.1
--------------------------------------------------------------------------

Note: 1% aqueous solution of potassium phosphate, pH 11, 20øC, 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 the
carbon chain of the substituent at the carbonyl group (Table 3). Whereas
the current yield of 2-(N-methylamino)butane amounted to 60.8% for
2-butanone, in the case of 2-hexanone under the same conditions the
corresponding secondary amine was formed with a yield of 35.0%. Branching
of the chain in the substituent at the carbonyl group or its substitution
by a phenyl radical led to a decrease in the yield. In addition to the
above-mentioned decrease in the yield of the secondary amines in the
amination of various ketones there was a general decrease in the reduction
rate, as clearly seen from the increase in the yield of hydrogen, which
amounted to 20.5% in the amination of 2-butanone, 49.5% in the case of
2-hexanone, and 75.1% in the amination of 3,3-dimethyl-2-butanone. For
3-pentanone the yield of the secondary amine amounted to only 18.2% with
respect to current, but compared with methyl ketones a significant amount
of the alcohol was formed, and its current yield amounted to 30.0%

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
ethylamine the yield of the required product decreased (cf. Tables 3 and 4)
with increase in the number of carbon atoms in the molecule of the primary
amine. Such a relationship shows up particularly clearly in the case of the
amination of 2-butanone, for which the secondary amines were obtained with
yields of 60.8, 51.0, and 43.0% respectively. The presence of a branched
chain in the carbon radical or the introduction of a phenyl radical at the
alpha position to the amino group led to an even larger decrease in the yield.

Thus, during the alkylation of isopropylamine by 2-propanol the required
product was formed with a yield of 29-35% with respect to current, while
the yield in the case of the alkylation with acetylbenzene was not greater
than 15-20%.

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

--------------------------------------------------------------------------
                        Secondary
    Ketone                amine         Alcohol         Hydrogen
--------------------------------------------------------------------------
2-Propanone                62.0           5.26            6.58
2-Butanone                 60.8           6.48            20.5
2-Hexanone                 34.8            -              49.5
3,3-DiMe-2-butanone         9.0            -              75.0
Acetylbenzene              18.9            -              42.1
3-Pentanone                18.2           31.0            37.9
Cyclopentanone             57.3           13.9            20.5
eyclohexane                70.3           3.73            8.58
2-Me-cyclopentanone        58.5           2.39            28.9
--------------------------------------------------------------------------
Note: The cathode was lead, aquous solution of Potassium phosphate, pH 12,
      current density 0.0397 A/cm2, 18-20øC, 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

--------------------------------------------------------------------------
                        Secondary
        Ketone            Amine         Alcohol         Hydrogen
--------------------------------------------------------------------------
2-Propanone               55.0           22.0             3.74
2-Butanone                51.0           31.4             5.0
3-Pentanone               11.8           45.5            39.9
Cyclopentanone            55.6            6.7             9.3
Cyclohexanone             44.0           32.7             6.87
2-Me-1-cyclopentanone     47.6           11.0            24.0
--------------------------------------------------------------------------
Note: The cathode was lead, 1N potassium phosphate solution, pH 12, current
      density 0.0397 A/cm2, 18-20øC.


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 side
reactions is determined by the electrochemical activity of the ketone. In
the case of readily reduced ketones with a low azomethine formation rate
the process is accompanied by the production of the alcohol, and for
difficulty reduced ketones it is accompanied by the release of hydrogen.
The amount of alcohol formed increases in the series of tested electrode
materials Cd < Pb < Zn < Cu. and this is probably due to the concurrent
adsorption of azomethine and ketone.

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.


                                EXPERIMENTAL

The electrolysis products were analyzed by GLC on an LKhM-8MD chromatograph
(column length 3 m, helium, 30 cm3/min, stationary phase TNDS-TM, mobile
phase octadecyl alcohol 10%, potassium hydroxide 5%).

The 25% aqueous solution of methylamine, the 42% aqueous solution of
ethylamine, the ketones, and the other arnines used in the experiments were
of pure and analytical grades. Before the experiments they were distilled,
and fractions boiling in a range of 1-2_C were collected. The other
reagents used for the experiments were of pure and analytical grades. The
characteristics of the obtained secondary amines were given in Table 5.

Preparation of Cathodes. Before the experiment the lead electrode was
treated two or three times with 5-10% nitric acid, washed with cold water,
and brushed. The cadmium electrode was treated two or three times with
5-10% oitric acid and wiped with soda after each treatment. Before the
experiment the copper electrode was treated with 10- 15% nitric acid and
washed with water. The tin electrode was treated with concentrated
hydrochloric acid and washed with water. The graphite cathode was
mercurized electrochemically in an acidified solution of mercuric nitrate.

For electrolysis 90 ml of a 1N solution of disubstituted potassium
phosphate and 0.42 mole of the primary amine was loaded into the cathode
compartment of a compartmentalized electrolysis cell fitted with a stirrer,
a thermometer and a cooling jacket. Concentrated potassium hydroxide
solution was added to the obtained mixture to pH 12, and 0.35 mole of the
ketone was added. A 40-ml portion of 2596 aqueous phosphoric acid was then
added to the anode compartment. Lead electrodes were used as cathode and
anode. Electrolysis was conducted by passing the theoretically required
amount of electricity and maintaining a temperature of 20-25_C and pH 12 in
the catholyte. The cathodic current density was 0.02-0.04 A/cm2. For the
isolation of the electrolysis products at the end of electrolysis the
reaction mass was neutralized to pH 7 with concentrated phosphoric acid,
and the obtained solution was extracted with methylene chloride to extract
the residual ketone and alcohol. The extracts were dried with magnesium
sulfate, the solvent was distilled, and the residue was distilled. The
aqueous solution after extraction was saturated with potassium hydroxide.
The separated amine layer was removed and further purified with solid
potassium hydroxide, after which it was distilled.

LITERATURE CITED

 1) V. S. Emersen, Organic Reactions [Russian translation], Vol. 5, IKhL,
    Moscow (1954), p. 342.
 2) V. I. Nekrasov and N. I. Shuikin, Usp. Khim., 34, No. 6, 1945 (1965).
 3) German patent 143197 (1903). I. Houben, Methods of Organic Chemistry
    [Russian transl.], Vol. 11, No. 1, Moscow, Leningrad (1941), p. 475.
 4) H. Muto, E. Ichikawa, and K. Odo, Denky Kagaku, 36, 363-368 (1968);
    Chem. Abs., 70, 25171q (1969).
 5) I. V. Kirilyus, V. A. Mirzoyan, and D. V. Sokolskii, Elektrokhimiya,
    10, No. 5, 858-860 (1974).
 6) E. A. Jeffery and A. Meisters, Aust. J. Chem., 31, No. 1, 73-78 (1978).
 7) E. A. Jeffery, O. Johnston, and A. Meisters, Aust. J. Chem., 13, No. 1,
    79-84 (1978).
 8) H. Lund, Acta Chem. Scand., 13, No. 3, 249-262 (1959).
 9) M. Matsuoka, M. Imaji, T. Shirakura, and N. Sugimoto, Denky Kagaku, 36,
    369-372 (1968); Chem. Abs., 70, 25176v (1967).
10) R. A. Benkeser and S. J. Mels, J. Org. Chem., 35, No. 1, 261-262 (1970).

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