Manufacture of N-arylglycinonitriles

Manufacture of N-arylglycinonitriles by reacting N-arylamines with carbonyl compounds and hydrogen cyanide under specific reaction conditions in respect of the temperature, reaction time and hydrogen cyanide concentration. The N-arylglycinonitriles obtainable by the process of the invention are antioxidants and valuable starting materials for the manufacture of dyes, fungicides, bactericides, textile assistants and as inhibitors for use in antifreezes.

The present invention relates to a process for the manufacture of 
N-arylglycinonitriles by reacting N-arylamines with carbonyl compounds and 
hydrogen cyanide under specific reaction conditions in respect of the 
temperature, reaction time and hydrogen cyanide concentration. 
German Pat. No. 656,350 discloses that glycollic acid nitrile can be 
reacted with excess methylamine in aqueous solution under pressure, to 
give sarcosinonitrile. An excess of up to 10 moles of methylamine per mole 
of hydroxyacetonitrile is recommended in order to achieve good yields of 
sarcosinonitrile (German Pat. No. 656,350). If stoichiometric amounts are 
used, considerable amounts of the nitrile of methyldiglycollamic acid are 
formed, and this compound is difficult to remove. 
Another method of preparation of N-alkyl-substituted glycinonitriles uses 
formaldehyde, in the presence of sodium bisulfite compounds, as the 
starting material, the aldehyde being reacted with sodium cyanide and 
aliphatic amines. Using sodium cyanide and sodium bisulfite presents 
environmental problems when the method is carried out industrially, on 
account of the formation of alkali metal salts, which may contain residual 
cyanides, as by-products. The use of the amines in the form of salts, eg. 
hydrochlorides has also already been proposed (Jean Mathieu and Jean 
Weil-Raynal, Formation of C--C Bonds, volume I, pages 442-446 (Georg 
Thieme Verlag, Stuttgart 1973)). 
All these methods are unsatisfactory from the point of view of simple and 
economical operation, good yields of end product and ease of working up 
and also in particular in respect of protection of the environment and 
purification of waste water. 
German Laid-Open Application DOS 1,543,342 discloses the continuous 
reaction of aniline with formaldehyde and hydrogen cyanide at from 
80.degree. to 130.degree. C., followed by hydrolysis of the reaction 
mixture with alkali metal hydroxide. Phenylglycinonitrile itself is not 
isolated. The patent application states that in general less than 10%, and 
frequently only from 1 to 5%, of the hydrogen cyanide and the formaldehyde 
are present in the free form in the reaction mixture. In none of the 
Examples is free hydrogen cyanide used. 
We have found that N-arylglycinonitriles of the formula 
##STR1## 
where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be identical or different 
and each is an aromatic radical, R.sup.3 and R.sup.4 may also each be 
hydrogen or an aliphatic, cycloaliphatic or araliphatic radical and 
R.sup.2 may also be hydrogen, are obtained advantageously if N-arylamines 
of the formula 
##STR2## 
where R.sup.1 and R.sup.2 have the above meaning, are reacted with 
carbonyl compounds of the formula 
##STR3## 
where R.sup.3 and R.sup.4 have the above meaning, and hydrogen cyanide in 
the presence of water for from 0.1 to 4 hours at from 0.degree. to 
80.degree. C., the concentration of hydrogen cyanide during the reaction 
being not more than 0.9% by weight, based on the reaction mixture. 
Where aniline and formaldehyde are used, the reaction may be represented by 
the following equation: 
##STR4## 
Compared with the process disclosed in German Laid-Open Application DOS 
1,543,342, the process of the invention gives N-arylglycinonitriles more 
simply and more economically, in better yield and higher purity. The 
process is particularly suitable for operation on an industrial scale and 
for continuous operation, presents no substantial waste water problems and 
gives virtually no resinous by-products which, at fairly high reaction 
temperatures, are preferentially formed, due to the presence of 
formaldehyde. All these advantageous properties are surprising in view of 
the prior art. 
Formaldehyde may be used in the liquid form or as a gas, but is in general 
used in the form of its aqueous solution, advantageously of from 10 to 50 
percent strength by weight and preferably of from 30 to 40 percent 
strength by weight. Hydrogen cyanide may be used as the gas or, 
advantageously, in the liquid form or in aqueous solution. The starting 
amine II may be used preferably by itself or in solution, advantageously 
in an organic solvent. The use of solutions of from 40 to 60 percent 
strength by weight is advantageous. The three starting materials may be 
reacted in stoichiometric amounts, or with any of the components in 
excess; preferably the conditions correspond to an excess, over the 
stoichiometric amount, of from 0.1 to 5 moles of amine, preferably from 
0.5 to 1 mole of amine, and/or from 0.01 to 0.1 mole of hydrogen cyanide 
per mole of carbonyl compound III. Preferred starting materials II and III 
and accordingly preferred end products I are those where R.sup.1, R.sup. 
2, R.sup.3 and R.sup.4 may be identical or different and each is phenyl or 
naphthyl, R.sup.3 and R.sup.4 may in addition each be hydrogen, alkyl of 1 
to 20, preferably of 1 to 8, and especially of 1 to 4, carbon atoms, 
alkenyl of 2 to 20, preferably of 2 to 8, carbon atoms, cycyloalkyl of 5 
to 8 carbon atoms or aralkyl of 7 to 12 carbon atoms, and R.sup.2 may in 
addition be hydrogen. The above radicals may in addition be substituted by 
groups and/or atoms which are inert under the reaction conditions, eg. 
nitro, hydroxyl or cyano, or alkyl or alkoxy each of 1 to 4 carbon atoms, 
or chlorine or bromine which are substituents of a phenyl nucleus. 
The following are examples of suitable starting materials III: 
formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, 
isobutyraldehyde, 2-methylbutyraldehyde, 2-ethylcapronaldehyde, 
n-valeraldehyde, isovaleraldehyde, 2,2-dimethylpropionaldehyde, 
2,2-dimethyl-3-hydroxypropionaldehyde, n-capronaldehyde, 
iso-capronaldehyde, 2-methylvaleraldehyde, 3-methylvaleraldehyde, 
2-ethylbutyraldehyde, 2,2-dimethylbutyraldehyde, 
2,3-dimethylbutyraldehyde, 3,3-dimethylbutyraldehyde, enanthaldehyde, 
2-methylcapronaldehyde, 3-methylcapronaldehyde, 4-methylcapronaldehyde, 
5-methylcapronaldehyde, 2-ethylvalderaldehyde, 2,2-dimethylvaleraldehyde, 
3-ethylvaleraldehyde, 3,3-dimethylvaleraldehyde, 
2,3-dimethylvaleraldehyde, 4-ethylvaleraldehyde, 
4,4-dimethylvaleraldehyde, 3,4-dimethylvaleraldehyde, 
2,4-dimethylvaleraldehyde, 2-ethyl-2-methylbutyraldehyde, 
phenylacetaldehyde, acetone, methyl ethyl ketone, methyl n-propyl ketone, 
methyl isopropyl ketone, methyl n-butyl ketone, methyl sec.-butyl ketone, 
methyl tert.-butyl ketone, methyl n-pentyl ketone, methyl pentyl-2 ketone, 
methyl pentyl-3 ketone, methyl isoamyl ketone, methyl(2-methyl)-butyl 
ketone, methyl(1-methyl)-butyl ketone, methyl(2-ethyl)-butylketone, 
methyl(3-ethyl)-butyl ketone, methyl(2,2-dimethyl)-butyl ketone, 
methyl(2,3-dimethyl)-butyl ketone and methyl(3,3-dimethyl)-butyl ketone; 
corresponding unsymmetrical ketones which contain phenyl, benzyl, 
cyclohexyl, ethyl, n-propyl, isopropyl or n-butyl instead of methyl; 
diethyl ketone, di-n-propyl ketone, di-isopropyl ketone, di-n-butyl 
ketone, di-iso-butyl ketone, di-sec.-butyl ketone, di-tert.-butyl ketone, 
di-n-pentyl ketone, dipentyl-2 ketone, dipentyl-3 ketone, diisoamyl 
ketone, di-(2-methyl)-butyl ketone, di-(1-methyl)-butyl ketone, 
di-(2-ethyl)-butyl ketone, di-(3-ethyl)-butyl ketone, 
di-(2,2-dimethyl)-butyl ketone, di-(2,3-dimethyl)-butyl ketone, 
di-(3,3-dimethyl)-butyl ketone, dicyclohexyl ketone, dibenzyl ketone and 
benzophenone. 
Examples of suitable starting materials II are methyl-, ethyl-, n-propyl-, 
isopropyl-, n-butyl-, isobutyl-, sec.-butyl- and 
tert.-buty-.alpha.-naphthylamine and -.beta.-naphthylamine, the alkyl 
substituent being in the 3-, 4-, 5-, 6-, 7-, 8- or 2- or 1-position, 
preferably in the 2-, 4- or 5-position; corresponding methyl, ethyl, 
n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl ethers 
of the .alpha.- and .beta.-naphthylamines which have a hydroxyl group in 
the above positions; .alpha.- and .beta.-naphthylamine disubstituted in 
the 3,4-, 4,5-, 4,8-, 5,8- or 6,7-position by methyl, ethyl, n-propyl, 
isopropyl, n-butyl, isobutyl-, sec.-butyl or tert.-butyl; corresponding 
dihydroxynaphthalenes in which 2 hydroxyl groups in the stated positions 
are etherified by the above alkyl groups; corresponding .alpha.- and 
.beta.-napthylamines with 2 of the above radicals which are, however, 
different from one another, eg. 4-ethyl-8-ethoxy-2-naphthylamine and 
4-methyl-5-methoxy-1-naphthylamine; 2-methylaniline, 3-methylaniline, 
4-methylaniline, 2-methoxyaniline, 3-methoxyaniline, 4-methoxyaniline, 
2,3-dimethylaniline, 3,4-dimethylaniline, 2,6-dimethylaniline, 
3,5-dimethylaniline, 2,3-dimethoxyaniline, 3,5-dimethoxyaniline, 
3,5-dimethoxyaniline, 2-ethylaniline, 3-ethylaniline, 4-ethylaniline, 
2,3-diethylaniline, 3,4-diethylaniline, 2,6-diethylaniline, 
3,5-diethylaniline, 2-ethoxyaniline, 3-ethoxyaniline, 4-ethoxyaniline, 
2-n-propylaniline, 3-n-propylaniline, 4-n-propylaniline, 
2,3-di-n-propylaniline, 3,4-di-n-propylaniline, 2,6-di-n-propylaniline, 
3,5-di-n-propylaniline, 2-isopropylaniline, 3-isopropylaniline, 
4-isopropylaniline, 2-butylaniline, 3-butylaniline, 4-butylaniline, 
2-isobutylaniline, 3-isobutylaniline, 4-isobutylaniline, 
2-tert.-butylaniline, 3-tert.-butylaniline, 4-tert.-butylaniline, 
2,3-diethoxyaniline, 3,4-diethoxyaniline, 2,6-diethoxyaniline, 
3,5-diethoxyaniline, 2,3,4-, 3,4,5-, 2,4,6-, 2,3,6- and 
2,3,5-trimethylaniline, 2,3,4-, 3,4,5-, 2,4,6-, 2,3,6- and 
2,3,5-trimethoxyaniline, 2,3,4-, 3,4,5-, 2,4,6-, 2,3,6- and 
2,3,5-triethylaniline and 2,3,4-, 3,4,5-, 2,4,6-, 2,3,6- and 
2,3,5-triethoxyaniline; anilines monosubstituted or polysubstituted in the 
above positions by hydroxyl, nitro, chlorine and/or bromine instead of the 
above alkyl substituents or together with the above alkyl substituents; 
and N-arylamines disubstituted by the above phenyl radicals and/or 
naphthyl radicals; diphenylamine, .alpha.-naphthylamine, 
.beta.-naphthylamine, .alpha.- or .beta.-naphthylamine substituted 
respectively in the 2- or 1-position, or in the 4-position, by methyl, 
ethyl or n-propyl, 2-methylaniline, 3-methylaniline, 4-methylaniline, 
4-methylaniline, 2,3-dimethylaniline, 3,4-dimethylaniline and especially 
aniline are preferred. 
The reaction is carried out at from 0.degree. to 80.degree. C., in general 
at between 0.degree. and 80.degree. C., advantageously from 40.degree. to 
80.degree. C., preferably from 45.degree. to 75.degree. C. and especially 
from 50.degree. to 70.degree. C., under reduced pressure, superatmospheric 
pressure or, preferably, atmospheric pressure, batchwise or, preferably, 
continuously. Water is advantageously used in the form of aqueous 
formaldehyde solution and/or aqueous amine solutions and in addition water 
is formed in the reaction itself; a total of from 1 to 6, preferably from 
3 to 4, moles of water, based on per mole of carbonyl compound III, may be 
used. Hydrogen cyanide is added to the starting mixture, before and during 
the reaction, in an amount such that the concentration of hydrogen 
cyanide, based on the reaction mixture during the reaction, does not 
exceed 0.9 percent by weight, and is in general from 0.01 to 0.9, 
advantageously between 0.01 and 0.9, preferably from 0.01 to 0.8 and more 
particularly from 0.01 to 0.7 percent by weight. The concentration of 
hydrogen cyanide, based on the reaction mixture during the reaction, 
particularly preferentially does not exceed 0.1 percent by weight and is 
preferably from 0.01 to 0.1 and especially from 0.05 to 0.1 percent by 
weight. The reaction time (or, in continuous operation, the residence 
time) is from 0.1 to 4 hours, preferably from 1 to 2 hours. The use of 
water as the sole solvent is preferred, but organic solvents which are 
inert under the reaction conditions may also be present. Examples of 
suitable solvents are aromatic hydrocarbons, eg. toluene, benzene, 
ethylbenzene, o-, m- and p-xylene, isopropylbenzene and methylnapthalene; 
aliphatic or cycloaliphatic hydrocarbons, eg. heptane, .alpha.-pinene, 
pinane, nonane, gasoline fractions within a boiling range of from 
70.degree. to 190.degree. C., cyclohexane, methylcyclohexane, petroleum 
ether, decalin, hexane, naptha, 2,2,4-trimethylpentane, 
2,2,3-trimethylpentane, 2,3,3-trimethylpentane and octane; and 
corresponding mixtures. The solvent is advantageously used in an amount of 
from 40 to 10,000 percent by weight, preferably from 50 to 1,500 percent 
by weight, based on starting material III. 
The reaction may be carried out as follows: a mixture of the carbonyl 
compound III, hydrogen cyanide and starting amine II, with or without 
water and/or organic solvent, is kept at the reaction temperature for the 
reaction time. Some of the hydrogen cyanide is introduced into the 
starting mixture and some is added during the reaction, in portions or 
continuously, so that the above concentration of hydrogen cyanide is 
maintained during the entire reaction time. The continuous measurement of 
the hydrogen cyanide concentration is advantageously carried out by means 
of a silver/calomel electrode. The end product is then isolated from the 
reaction mixture by conventional methods, eg. by distillation or by 
extraction, eg. with cyclohexane, followed by distillation of the solvent. 
The N-arylglycinonitriles obtainable by the process of the invention are 
antioxidants and valuable starting materials for the manufacture of dyes, 
fungicides, bactericides, textile auxiliaries and inhibitors for use in 
antifreezes. Alkali metal salts of phenylglycine are used as starting 
materials for the synthesis of indigo. With regard to the use of the 
compounds, reference may be made to the above German Laid-Open Application 
and to Ullmanns Encyklopadie der technischen Chemie, volume 9, page 388, 
volume 15, page 219, and volume 19, pages 300, 317 and 339.

In the Examples which follow, parts are by weight. 
EXAMPLE 1 
Per hour, 400 parts of 30 percent strength by weight aqueous formaldehyde 
solution, 108 parts of liquid hydrogen cyanide and 372 parts of aniline 
are slowly mixed in a stirred kettle at 65.degree. C.; the hydrogen 
cyanide concentration in the reaction space does not exceed 0.9 percent by 
weight (based on the reaction mixture), and averages 0.8 percent by 
weight. After a mean residence time of 60 minutes, the reaction mixture is 
passed into a reactor which is at 65.degree. C. The mean residence time in 
the reactor is 45 minutes and the average hydrogen cyanide concentration 
is 0.5 percent by weight. Per hour, 880 parts of a reaction mixture are 
obtained; this is extracted with benzene and after evaporation of the 
benzene gives, per hour, 512 parts (98% of theory) of phenylglycinonitrile 
of n.sub.D.sup.50 =1.5591 and melting point 40.degree.-42.degree. C. 
(after recrystallization from a 1:1 mixture of cyclohexane and 
isopropanol). 
EXAMPLE 2 
Per hour, 400 parts of 30 percent strength by weight aqueous formaldehyde 
solution, 108 parts of liquid hydrogen cyanide and 372 parts of aniline 
are slowly mixed in a stirred kettle at 65.degree. C.; the hydrogen 
cyanide concentration in the reaction space does not exceed 0.1 percent by 
weight (based on the reaction mixture), and averages 0.08 percent by 
weight. After a mean residence time of 60 minutes, the reaction mixture is 
passed into a reactor which is at 65.degree. C. The mean residence time in 
the reactor is 45 minutes and the average hydrogen cyanide concentration 
is 0.04 percent by weight. Per hour, 880 parts of a reaction mixture are 
obtained; this is extracted with benzene and after evaporation of the 
benzene gives, per hour, 512 parts (98% of theory) of phenylglycinonitrile 
of n.sub.D.sup.50 =1.5591 and melting point 40.degree.-42.degree. C. 
(after recrystallization from a 1:1 mixture of cyclohexane and 
isopropanol).