804 ELLIOTT : THE APPLICATION O F THE

XCV.-The Application of the Hofmann Reaction to Substituted Carbamides.

By GEORGE ROBERT ELLIOTT, SINCE in the reaction between alkali and benzochloroamide the Hofmann reaction proceeds under easily controlled conditions (Elliott, T., 1922, 121, 202), the possibility of its occurrence with an N-chlorocarbamide under similar conditions has been investigated.

The N-chloro-compounds of phenylcarbamide were selected for this purpose as likely to give less complex reactions than the analogous derivatives of carbamide itself, owing to the presence of the stabilising phenyl group, and the unsymmetrical structure of the molecule.

According to Doht (Monatsh., 1906,27,213), the action of chlorine in excess on phenylcarbamide in cold acetic acid solution produces 2 : 4-dichlorophenylcarbamide ; whilst 2 : 4 : 6-trichloroacetanilide, ammonium chloride, and carbon dioxide are produced a t higher temperatures.

Chattaway and Chaney (T., 1910, 97, 292), without mention of Doht’s experiments, in a much more comprehensive study of the action of chlorine on phenylcarbamide in glacial acetic acid solution, obtained different results from those of the earlier investigator. By variation of the conditions, they substituted chlorine for one, two, or three of the hydrogen atoms attached to nitrogen, in the order,

and in presence of hydrogen chloride, isomerisation of the -CO*NC1*C6H, group to -CO*NHeC6H,c1 occurred ; the first chlorine atom passes into the para-position, and subsequent atoms then take up the two ortho-positions. Chattaway and Chaney also drew the conclusion that the -CO-NHCl group was comparatively stable towards hydrochloric acid, but broke down in presence of alkali carbonates, liberating nitrogen.

The first claim to the successful application of Hofmann’s reaction

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online / Journal Homepage / Table of Contents for this issue

'FTOFMANN REACTION TO SUBSTITUTED CARBAMIDES. 805

to a carbamide was put forward by Schestakoff ( J . Russ. Phys. Chem. Soc., 1905, 37, 1) when he obtained hydrazine from urea by the action of equivalent quantities of alkali hypochlorite and hydroxide.

NH,*CO*NH, -+ NH,*C(ONa):NCl --+ NH,*N:CCl( ONa) --+ NH,*NHCO,Na ?$ NH,*NH, + NaHCO,.

Werner (T., 1922, 121, 2324), however, from evidence obtained in his investigations on the hypochlorite method of estimating urea, has been led to doubt whether this mechanism can be accepted as applying to more than a possible side reaction.

The experiments described in the present communication tend to support Schestakoff's view that the transformation is analogous to the Hofmann reaction.

Chattaway (T., 1909, 95, 235) discovered that the action of ammonium hydroxide on dichlorocarbamide, NHCICOeNHCl, pro-

The suggested mechanism of the reaction was : NaOCl NaOH

-

NH*NR>CO; he suggested that mono- duced p-urazine, CO<NH.NH chlorocarbamide was first formed, and under the influence of ammonia was then converted into the urazine by direct candensation, with loss of hydrogen chloride :

In the author's opinion, however, the change is another instance of the Hof mann reaction, according to the mechanism

NH,*C(OH):NCl ?!?? NH,*C( ONHJNC1 -+ NH2*N:C(ONH4)C1 -+ NH,*N:CO + NH,CI.

As it was unlikely that the intermediate compounds could be isolated, support of this view seemed to require the proof that chlorocarbamides in general react with alkalis through intermediate carbimide compounds.

The results actually obtained by the action of sodium hydroxide, ammonium hydroxide, or sodium ethoxide on phenylmonochloro- carbamide, C,H,*NHCO*NHCl, and on mono- and tri-chlorophenyl- monochlorocarbamides are diflicult to explain on any other assump- tion. For instance, the action of ammonium hydroxide on p-chloro- phenylmonochlorocarbamide produces p-chlorophenylsemicarbazide, C,H,Cl*NH*NH*CO*NH,. This reaction requires for its simple

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

806 ELLIOTT : THE APPLICATION OP THE

explanation the intermediate formation of a carbimide following a Beckmann change, thus :

R*NH*C(OH):NCl NH,y R*NH*C( ONH,):NCl -+ R*NH*N:C( ONH,)Cl --f R*NH*N:CO 25: R*NH*NH*CO*NH,.

The action of the other alkalis is similarly explicable on the lines of Hofmann’s reaction.

Another surprising and important result came to light in connexion with the preparation of the chlorophenylcarbamides. It was observed that not only can a chlorine atom wander from the nitrogen atom directly attached to the nucleus of a phenylchloro- carbamide, C6~15*NC1*CO*NHC1, for example, giving p-chloro- phenylchlorocarbamide, C,H,Cl*NH*CO*NHCl, but also that when the phenyl group is unsubstituted, a chlorine atom may wander to the para-position, from the nitrogen atom indirectly attached to the nucleus. Thus, under the influence of alkali in the cold, or by boiling the aqueous solution, pchlorophenylcarb- amide, C6H4C1*NH*CO*NH,, was obtained from phenylmonochloro- carbamide, C6H5*NH*CO*NHC1. If the para-position be already occupied, no such wandering to the ortho-position will occur ; thus a second atom of chlorine could not be introduced into the nucleus by treatment of p-chlorophenylmonochlorocarbamide,

c ,H4C1*NH*CO*NHC1. This limitation differentiates the wandering from that which takes place from the nitrogen atom directly attached to the nucleus, and indicates that a t no period of the transition does the chlorine atom become linked to this nitrogen atom.

E X P E R I M E N T A L . Chlorination of Phenylcarbamide.-As it was immaterial to the

present purpose whether the benzene nucleus were substituted or not, provided a chlorocarbamide containing the group -NHCO-NHCl were obtained, the direct chlorination of phenylcarbamide in aqueous solution was studied. Analyses of the products showed that, under such conditions, mixtures of mono-, di-, and tri-chloro- phenylchlorocarbamides are formed according to varying degrees of acidity and duration of chlorination. By the action of sul- phurous acid on the mixed products, a t least two consecutive members of the series phenylcarbamide, p-chlorophenylcarbamide, 2 : 4-dichlorophenylcarbamide, and 2 : 4 : 6-trichlorophenylcarb- amide are usually obtained, but their separation by fractional crystallisation is too tedious to make the preparation of any particular one of them practicable by this method.

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

HOEMANN REACTION TO SUBSTITUTED CARBAMIDES. 807

Turning to published methods of preparation of the chloro- carbamides, the author drew the conclusion that Chattaway and Chaney (Zoc. cit.) underestimated the effect of hydrochloric acid on the -CO*NHCl group. Concentrated hydrochloric acid causes evolution of chlorine from all the plienylchlorocarbamides containing such a group; and although the action is slow with dilute acid, it certainly takes place. Thus if phenylcarbamide be completely chlorinated in concentrated hydrochloric acid solution, using a moderately slow stream of chlorine, 2 : 4 : 6-trichlorophenylcarb- amide only will be obtained, and no chlorine attached to nitrogen will be detectable in the product. Owing to the hydrogen chloride liberated during substitution, a similar action takes place when the chlorination is conducted in indifferent solvents; this to some extent causes uncertainty in repeating the carefully worked-out preparations of Chattaway and Chaney if a slower stream of chlorine than that used by these experimenters be employed. I n repeating their preparation of 2 : 4 : 6-trichlorophenylmonochlorocarbamide, C,H,Cl,~NK*CO*NHCl, which, being the ultimate product of direct chlorination in acetic acid solution, is given as the most easily pre- pared of the chlorophenylchlorocarbamides, the author carefully fulfilled the prescribed conditions of concentration and temperature. After chlorination for two hours, no product had separated, and on adding water, a mixture containing very little chlorine attached to nitrogen, and consistling mainly of 2 : 4 : 6-trichlorophenyl- carbamide, was obtained. Too slow a stream of chlorine had, evidently, been employed, so that chlorine was removed from the -CO*NHCl group as quickly as it was introduced.

A similar explanation, no doubt, accounts for the failure of Doht (Zoc. cit.) to obtain a chlorocarbamide, although his statement that 2 : 4-dichlorophenylcarbamide is produced by the action of excess of chlorine on phenylcarbamide in cold acetic acid solution is incorrect.

As direct chlorination of phenylcarbamide offered such difficulties of control, the use of N/5-hypochlorous acid was resorted to. By this means, in the cold and in absence of hydrochloric acid, chlorine atoms are introduced in the order given on p. 804.

As, however, the reaction between a carbamide and hypochlorous acid is reversible, an excess of the latter reagent is required for the completion of each of these stages; a 10 per cent. excess of N / 5 - hypochlorous acid was employed in each case, although this amount does not displace the equilibrium in any reaction to the completion point. It was desirable, however, to underchlorinate rather than to overchlorinate, as the presence of unchanged carbamide does not affect the result of the action of alka,lis, reversion to carbamide

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

808 ELLIOTT : THE APPLICATION OF THE

being one of the normal courses of such reaction with the chloro- carbamide.

Preparation of Phenylmonochlorocarbamide, C6H5-NH*CO*NHCl.- The requisite amount of hypochlorous acid is allowed to remain in contact with a suspension of finely ground phenylcarbamide during several hours. The oily emulsion which first forms soon coagulates to yellow nodules of crude phenylmonochlorocarbamide.

Treated with cold hydrochloric acid, this compound loses chlorine , and phenylcarbamide is obtained ; consequently the chlorine atom is combined with the nitrogen atom indirectly attached to the nucleus, otherwise isomerism to p-chlorophenylcarbamide would occur. If , however, this chlorocarbamide be warmed with water, chlorine will wander from the side chain to the para-position in the nucleus ; in the cold, no p-chlorophenylcarbamide could be detected even at the end of twenty-four hours,

Preparation of p-Chlmop7Lenylcurbamide, C6H,C1*NII*COaNH,.-- Phenylcarbamide is treated with an aqueous solution of hypo- chlorous acid (1 mol.), and the solution heated to boiling. This does not serve to complete the transformation, but a repeated treatment with the acid (1 mol.) is more than sufficient to complete the change without introducing any further chlorine atoms into the nucleus of the p-chlorophenylcarbamide already present. Any chlorine attached to nitrogen is now removed with sulphur dioxide, and the brown solution decolorised with animal charcoal. p-Chloro- phenylcarbamide separates in needles from the cooled solution and after recrystallisation from water melts at 212".

A second atom of chlorine may be introduced into the nucleus only by causing it to wander from the nitrogen atom directly attached to the nucleus. Attempts were made to prepare 2 : 4-di- chloroplzenylcarbamide by treatment of p-chlorophenylcarbamide with two equivalents of hypochlorous acid to produce the com- pound C6H,C1*NC1aCO*NHC1, warming with a little hydrochloric acid to isomerise to 2 : 4-dichlorophenylmonochlorocarbamide, and then treating with sulphurous acid. Owing, however, to the complex equilibria between hypochlorous acid, the chlorophenylcarbamide, and the various possible chloro-compounds of mono-, di-, and tri- chlorophenylcarbamides, mixtures of mono- and di-, or of di- and tri-chlorophenylcarbamides were obtained in each case, and could only be separated by tedious fractional crystallisation.

Prepration of 2 : 4 : 6-Trichlorophenylcarbarnide, C,H,C&*NH*CO*NH,.

-This compound is most easily prepared by direct chlorination to completion of phenylcarbamide (10 grams), dissolved in a, mixture of glacial acetic acid (100 c.c.) and concentrated hydrochloric acid

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

HOFMANN REACTION TO SUBSTITUTED CARBAMIDES. 809

(100 c.c.). The product is precipitated with water, collected, and recrystallised from alcohol. Should the presence of any chlorine attached to nitrogen be indicated on testing with potassium iodide, the product is first treated with sulphurous acid.

Action of Alkalis on Phenylch~orocarbamide, C,H,*NH*CO*NHCl. -The preliminary reactions which take place in aqueous solution are represented by :

I. C6H,*NH*CO*NHC1 + H,O -z C,H,*NH*CO*NH, + HOCI.

111. C6H4C1*NHeCO*NH, -t HOCl?? C6H,C1*NH*CO*NHC1+H,0.

In each experiment, phenylcarbamide was formed (reaction I) : p-chlorophenylcarbamide was also produced under the influence of the alkali (reaction 11). The further product was actually the result of the action of alkali on p-chlorophenylmonochlorocarb- amide obtained according to reaction 111, and will be considered later. It will be seen that this removal of p-chlorophenylmono- chlorocarbamide causes each reaction to proceed from left to right by displacement of the equilibria.

The final products of the action of alkalis on phenylchlorocarb- amide are consequently identical with those obtained from p-chloro- phenylmonochlorocarbamide.

Action of Sodium Hydroxide.-On addition of sodium hydroxide solution t o phenylmonochlorocarbamide, C,H,*NH*CO*NHCl, there was a development of heat, an odour reminiscent of carbylamine, a darkening of the colour, and a vigorous evolution of nitrogen. The chlorocarbamide appeared to be more soluble in the alkali t'han in water, and the residue after filtration consisted mainly of phenylcarbamide and p-chlorophenylcarbamide. As it was the changes of the portion soluble in alkali, probably due to the pre- liminary formation of a compound R*NH*C(ONa):NCl, which were to be studied, the procedure in each experiment was to add tlhe alkali solution, stir, filter rapidly, and examine the filtrate, rejecting the residue.

The clear filt'rate soon became cloudy, and steam distillation yielded (a) a compound ($1-chlorophenylhydrazine) which reduced Fehling's solution and gave with benzaldehyde a compound which contained chlorine, ( b ) a yellow oil having the properties of chloro- benzene.

After separating these substances by filtration, the alkaline residue was acidified with hydrochloric acid; it gave a yellow precipitate (p-chlorobenzenediazocarboxylic acid and p-chloro- phenylhydrazinecarboxylic acid), which decomposed instantaneously with a vigorous gas evolution, leaving a pasty, yellow mixture of

11. C6H,*NH*CO*NHC1 -+ C6H4C1*NH*CO*NH2.

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

810 ELLIOTT : THE APPLICATION O F THE

products, amongst which chlorobenzene was identified, whilst the acid solution contained p-chlorophenylhydrazine, which separated on the addition of alkali.

Although each of these products was only formed in very small quantity, there is little doubt that Hofmann's reaction had taken place according to the following mechanism, where R = p-C6H,C1 :

I. R*NH.C(OH):NCl+ NaOH --+ R-NH*C(ONa):NCl+ H,O. 11. R*NHC( ONa):NCl+ R*NH*N:C( 0Na)Cl f R*NH.N:CO+NaCl.

111. R*NH-N:CO + NaOH -+ R-NH-NH-CO-ONa R*NH*NH, + NaIICO,.

The hydrazine formed would then be attacked by the sodium hypochlorite present in solution, giving the hydrocarbon which is the normal product of such action (Chattaway, T., 1909, 95, 1065). Complications also arise from the oxidation of the sodium p-chloro- phenylhydrazinecarboxylate, C6H4C1*NH*NH*C0,Na, to sodium p-chlorobenzenediazocnrboxylate, C6H4C1*N:N*C0,Na. The free diazo-acid decomposes immediately, giving a complex mixture of products, one of which is chlorobenzene.

Action of Ammonium Hydroxide.-Ammonium hydroxide was added to phenylmonochlorocarbamide, and the well-stirred solution was then immediately filtered. The residue consisted mainly of phenylcarbamide and p-chlorophenylcarbamide. The clear, orange- coloured filtrate, when allowed to stand, or more rapidly when warmed, deposited a yellow precipitate which reduced warin Fehling's solution. This product proved to be a mixture of two compounds separable by extraction with boiling benzene. The benzene extract deposited long, orange-red needles, which after recrystallisation melted at 182", whilst the insoluble portion was colourless, and after recrystallisation from acetic acid melted a t 233".

The insoluble, colourless product reduced boiling Fehling's solution, and gave, on hydrolysis, ammonia and colourless needles melting a t go", which readily reduced Fehling's solution in the cold. The compound (m. p. 233") was doubtless p-chlorophenyl- semicarbazide (Found : N = 22.7. C,H,0N3C1 requires N = 22.64 per cent.). The hydrolysis product (m. p. 90") was p-chlorophenyl: hydrazine .

On oxidation with alkaline permanganate, the chlorophenyl- semicarbazide gave p-chlorobenzenediazocarbonamide,

C,H,Cl*N:N*CO*NH, (m. p. 182O), which proved to be identical with the portion of the original product soluble in benzene.

The mechanism of the reactions giving these products is probably

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

HOFMANN REACTION TO SUBSTITUTED CARBAMIDES. 811

represented by the scheme shown on p. 806, and during the reaction some of the p-chlorophenylsemicarbazide is oxidised to p-chloro- benzenediazocarbonamide. It was found that p-chlorophenylsemicarbazide is very susceptible

to alkaline oxidising agents, and is, indeed, readily oxidised to the diazo-compound if left exposed to the air, in alkaline solution. An alcoholic solution of the semicarbazide rapidly became orange- red after the addition of ammonium hydroxide solution, and deposited long, orange needles of p-chlorobenzenediazocarbonamide after exposure to the air for several days.

When a solution of the semicarbazide in alcoholic potash is left exposed to the air, golden-yellow flakes appear after about two days. This compound is probably potassium p-chlorobenzene- diazocarboxylate, CGH4C1*N:N*C02K, as its properties and reactions agree in all respects with those of this salt as recorded by Hantzsch and Schultze (Ber., 1895, 28, 2081); its formation is doubtless due to hydrolysis following oxidation :

R*NH*NH*CO*NH, -+ R*N:N*CO*NH, + R*N:N*CO,K. Action of Potassium Ethoxide.-On the addition of potassium

ethoxide to an alcoholic solution of phenylmonochlorocarbamide, there was a, darkening of the solution and potassium chloride separated, followed after some time by a precipitate of golden- yellow plates. It was found impossible to purify this compound from potassium chloride, but in properties it appeared to be identical with the sample of potassium p-chlorobenzenediazocarboxylate prepared from p-chlorophenylsemicarbazide as described above. From analogy with previous results, the reaction probably proceeds along the lines

R*NH*C(OH):NCl+ R*NH*C(OK):NCI -+ R*NH-N:C( OK)CI-+ R*NH*N:CO + KCI.

R*NH*N:CO -+ EtOM + R*NH*NH*CO,Et. I n the presence of alkaline oxidising agents the hydrazo-compound would doubtless oxidise to the diazo-compound,

R*NH*NH*CO,Et + 0 -+ R*N:N*CO,Et + H,O, which by hydrolysis would give R-N:N*CO,K.

The view that the product is a diazo-compound and not a hydrazo- compound is based on its golden-yellow colour, which is not due to organic impurity; also on the fact that the free acid liberated from the potassium salt is obtained as a, yellow precipitate before it decomposes.

Action of Alkalis on 2 : 4 : 6-Trichloro~henylmonochlorocarbamide, C,H,CI,*NH*CO*NHCl.

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

812 THE APPLICATION OF THE HOFMANN REACTION, ETC.

Action of Sodium Hydroxide.--lf sodium hydroxide be added to the chlorocarbamide, and the product boiled and steam distilled, 2 : 4 : 6-trichlorobenzene will be obtained. If, however, the reaction be performed in the cold, other compounds may be isolated.

As before, the alkali was added, the mixture stirred and im- mediately filtered, and the filtrate and washings were examined.

On the addition of the alkali, heat was developed, and the solution darkened; in some cases, conditions favoured the separation of a brown precipitate of a sodium compound. On acidifying the solution with hydrochloric acid, a yellow precipitate (trichloro- benzenediazocarboxylic acid and trichlorophenylhydrazinecarb- oxylic acid) separated momentarily, but decomposed immediately with effervescence and production of a brick-red, pasty mass, from which s-trichlorobenzene was obtained on steam distillation. After Btration, the acid solution was made alkaline, and a colourless precipitate of 2 : 4 : 6-trichlorophenylhydraxine obtained. This com- pound crystallises from alcohol in long, flat needles melting a t 138" (Found : C1 = 50.19. C6H,NBC1, requires C1 = 50.36 per cent.). Its warm aqueous solution readily reduces Fehling's solution, and when boiled with copper sulphate gives s-trichloro- benzene. The hydrochZoride is readily soluble in water, but only slightly soluble in concentrated hydrochloric acid.

The mechanism of the reaction may be represented as in the production of p-chlorophenylhydrazine ; and, as in that case, oxidation to some extent diverts the main reaction, sodium tri- chlorophenylhydrazinecarboxylate giving sodium trichlorobenzene- diazocarboxylate,

C,H2CI,*NH*NHC0,Na + 0 -> C6H,C1,*N:N*C02Na + H,O. The brown precipitate which in some cases separated from the

original reaction mixture was probably the oxidation product , sodium 2 : 4 : 6-trichlorobenzenediazocarboxylate alone : when treated with acid, it gave a red, pasty mass, similar to that obtained as already described, and no hydrazine could be obtained from the resultant solution.

Action of Ammoniuqa Hydroxide.-The chlorocarbamide wa,s more soluble in ammonium hydroxide solution than in water, but on warming the clear solution, only 2 : 4 : 6-trichlorophenylcarbamide separated.

Action of Sodium Ethozide.-An alcoholic solution of sodium ethoxide was added to trichlorophenylmonochlorocarbamide ; the liquid was well stirred, and then filtered. The filtrate was dark coloured and deposited a flocculent precipitate. This compound, washed with alcohol, was quite colourless, did not melt, and was

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online

BOYD AND CH'I(3NELL : PHOSPHOROUS ACID ESTERS, 813

evidently sodium 2 : 4 : 6-trichlorophenylhydrazinecarboxylate, as i t dissolved readily in cold water to give a solution which, slowly when kept, more rapidly when warmed, deposited 2 : 4 : 6-trichloro- phenylhydrazine. Also, the cold aqueous solution, treated with hydrochloric acid, gave a precipitate which immediately decom- posed with effervescence, and from the solution, alkali then pre- cipitated trichlorophenylhydrazine.

The original alcoholic filtrate from the sodium trichlorophenyl- hydrazinecarboxylate contained the oxidation product, sodium trichlorobenzenediazocarboxylate ; after diluting with water, and filtering, the clear filtrate gave, when acidified with hydrochloric acid, a yellow precipitate which decomposed with effervescence, yielding a pasty mass containing s-trichlorobenzene.

The mechanism of the reactions giving these products is probably similar to that put forward for the action of potassium ethoxide on phenylmonochlorocarbamide .

In conclusion, the author wishes to express his indebtedness to Professor F. S. Kipping, F.R.S., for his continued interest and criticism of this work; also to acknowledge receipt of a grant from the Department of Scientific and Industrial Research which has enabled this investigation to be carried out. UNIVERSITY COLLEUE, NOTTINCHAM. [Received, February 20th, 1923.1

Publ

ishe

d on

01

Janu

ary

1923

. Dow

nloa

ded

by N

ew Y

ork

Uni

vers

ity o

n 26

/10/

2014

20:

20:2

4.

View Article Online