I The Reaction 1 with Nitrous of Tertiary Amines - ACS Publications

a romantic notion fostered in the act of eulogizing a particular scientist. The process of replacing an ac- credited theory with a new one has many st...
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George E. Hein Boston University Boston, Massachusetts

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The Reaction of Tertiary Amines with Nitrous Acid

T ~ x estudy of the history of science has made it evident that the acceptance of new theories is a complicated process. Older notions which suggested that a particular experiment "overthrew" an established concept and immediately opened the way t o a new one have been repeatedly challenged by careful examination of the historical record. It now appears that the overpowering influence of a critical experiment is often a romantic notion fostered in the act of eulogizing a particular scientist. The process of replacing a n accredited theory with a new one has many steps. First, there is a period of rapid incorporation of facts within an old framework. Gradually, as the facts fail to fit neatly, an expansiou and weakening of the framework occurs to accommodate new data. Next, or concurrently, may come a period where certain observations do not fit into the framework a t all. They may be noted in a branch of the science far removed from theoretical work. After some time, new suggestions emerge, often limited to a few examples or with concessions to the older theory. Finally, a unifying concept develops such appeal that it can overcome all opposition and gradually replace the older concept. Perhaps one should add that all this is a continuing process, every "new" concept becomes an old established one after some time and is vigorously defended against attacks by skeptics.

It is not difficult to understand the reasons for resistance to change. The appreciation of a concept is a long process. Once an idea is learned, accepted, and used, it is difficult to discard it and accept a new one which may or may not be more useful. I n discussing the origins of modern physics, Butterfield points out eloquently the difficulty of "putting on a new thinking cap (I)." Such revolutions in thinking do not occur often; it takes a remarkable man to be able to make the leap to a new concept. A further appreciation of the inertia of the intellect can be attained by examining more humble examples of resistance to change. Kot only new general concepts but even simple observations can have difficulty in becoming established if they are contrary to accepted notions. I n these latter cases, the resistance is not based on the desire to retain a useful belief; rather, it involves intellectual laziness, an unwillingness to make the effort to incorporate an unrelated fact into a crowded network of ideas. Contrary to popular belief, many scientists, like many people generally, suffer from a conservatism which causes them to resist conceptual changes. Most people try to simplify life. One way to do this is to recognize only part of the multitude of sensations which impinge upon us. Such selectivity is neczssary to order the universe. However, when applied to the

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conduct of an experiment, it often means that the investigator observes only the phenomena which have a direct relation to what he wants to discover. Probably most scientists are more likely to repeat an experiment which goes "wrong" rather than one which goes "right." I t is important to remember that these evaluative terms only have meaning within the framework of the particular scientist's knowledge, background, and interests. Early History

The conservatism which prevents scientists from recognizing as significant those experiments which are contrary to accepted beliefs is illustrated by the history of the reaction of tertiary amines with nitrous acid. This reaction is a well established phenomenon. It has been discussed vigorously in texts and papers since 1864; it has been independently "discovered" at least three times as a general reaction; and there arc many separate examples reported in the literature. Yet, the reaction is mentioned less often in each succeeding generation of texts: I n 1866 Heintz published a definitive paper (2) demonstrating that tertiary amines do not react with nitrons acid. He did this mainly to refute a paper by Guether (5) published two years earlier, in which it was reported that triethylamine gave some N-nitrosodiethylamine when treated with nitrous acid. Heintz found no evidence for this reaction and suggested that perhaps Guether's triethylamine was contaminated with some secondary amine. At that time the separation of the alkylation products of ammonia was difficult and his explanation is reasonable. Also his own experiments are sound and comprehensive. There is no reason to doubt his results. The now well known "inei%ness" (except for salt formation) of tertiary amines towards nitrous acid and the use of this reagent to separate classes of amines has been discussed as the "Heintz method" (4). Yet, only one year later, Limpricht (5) reported that nitrous acid did react with tribenzylamine in a complicated manner. No matter how he attempted to control conditions, the reaction took a variable course. Limpricht did succeed in partially identifying some reaction products. First, he noted that one product of the reaction was often henzaldehyde. He demonstrated that this was probably a primary product, rather than a biproduct derived from the oxidation of some primary benzylic compound, such as henzyl alcohol, under the reaction conditions. Secondly, in one attempt, he isolated a low melting solid from an oil which had collected above the reaction mixture. Although he failed to identify the solid, it was probably N-nitrnsodibenzylamine (6). Limpricht does not mention Heintz' paper, but he has taken precautions to be sure that his tribenzylamine was pure, uncontaminated by secondary amine. On the whole the two papers are comparable. Each is the result of careful work; starting materials are purified and experiments described in detail. Heintz comes out with a neater argument, but then he is reporting negative results. Limpricht cannot pin down the phenomenon he ohserves, but he did identify the major reaction products. Although nitrous acid became a tool for separating 182

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Journal of Chemical Education

secondary and tertiary amines, it mas more or less accepted that tertiary amines also reacted with this reagent. Influential texts, such as Meyer-Jacobson, (7) mentioned the reaction, and in 1896 Icishner (8) reported the preparation of N-nitroso-N-ethylmem thylamine from N,N-diethylmenthylamine and nitrons acid in weakly acid solution. He wrote equation .(I) for the reaction.

+

ClaH,JV(C2H& HNO?

-

+

ClaHlpN(C2Hs)N0 CzHsOH (1)

He commented, without reference, that "like inost aliphatic tertiary amines, diethylmenthylamine loses one of its radicals as an alcohol by the action of nitrous acid." Some years earlier, E. Schmidt (8) had attempted to purify trimethylanline by heating the crude compound with nitrons acid. He found to his disappointment, that the product was less pure than the starting material! Rediscovery i n 1920

Despite these reports, some of which are listed in Beilstein, the reaction essentially disappeared from the chemical literature. I t became so neglected that it was "discovered" in 1920 And patented by chemists at Merck and Co. (10). They were interested in methods of preparing N-nitroso compounds and were delighted to note that not only secondary amines hut even tertiary ones could he converted into the desired products despite the fact that "not only in all the texts, but even in colleges, one is taught that tertiary aliphatic amines do not react with nitrous acid." This patent received proper circulation and resulted in two general papers on the reaction. Degradative procedures for tertiary amines are of particular iuterest in alkaloid chemistry. Speyer and Walther (11); on the basis of the pateut, suggested that this reaction might replace the von Braun degradation which involves the reaction of cyanogen bromide with tertiary amines. They did not suggest a mechanistic analogy but a formal one. RzNR' RBNR'

+ BrCN

=

R2N-CN

+ BrR'

+ HONO = R2N-NO + (HOR')

(2)

(3)

They tried six examples chosen from the morphine alkaloids and, except for morphine itself, which is readily oxidized to a dimer by mild oxidizing agents, they succeeded in degrading morphine and codeine derivatives to N-nitroso products of the nor series. Almost simultaneously the method was used by Ochiai (12). These papers were the origin of a limited tradition of nitrosative degradation of alkaloids. Since then Abubakirov and Yunosov (15) and Cookson and Trevitt (14) have used it for certain lupine alkaloids. Probably the same reaction is involved in Craig's degradation of related compounds by nitrous and nitric acids (15), and in Goodson and Henry's nitrosation of echitamine (16). The latter reaction could not he repeated by Chatterjee ( 1 7 ) , who may have worked with more acid solutions. The set of papers just mentioned represents a sample from one branch of organic chemistry. The scope of organic chemistry is so great that workers in one research area may use reactions which are not generally known and which are not well understood. Thus, the

references in the papers on alkaloid chemistry are only to previous work in the same area; it is implied that this degradation is characteristic for alkaloids, not for tertiary amines generally. I n a similar manner, the evidence from one field of natural products research does not seem to have been noted by other chemists. In 1936 Wegler and Frank (18) published a definitive paper on the reaction, really the first except for Limpricht's contribution. Wegler and Frank came upon the reaction accidentally while trying to purify isoboruylamine. Like many others before them, they encountered difficulty with the nitrous acid procedure. Perhaps it was the readily detectable camphor, one of the products, which led them on. I n any case, they recognized what was going on and made a successful generalization. First, they attempted to survey the literature of this reaction. Although rather incon~plete, their bibliography did give some telling examples including the Merck patent. Secondly, they tried to rationalize the reaction. Without going into details, they pointed out the similarity to the von Braun reaction and to other degradative procedures for tertiary amines. Thirdly, they converted approximately a dozen tertiary amines into N-nitroso secondary amines and aldehydes or ketones. Yields of carbonyl con~poundswere 30 to 60% plns some recovery of starting materials. Finally, they apparently defined the proper reaction condition: most reactions were run a t 40' to 80' in acetic acid. Unfortunately, in the next year the same authors published a rather disappointing note (19) on attempts to use the reaction for some particular synthetic problems. For unknown reasons they had switched to a mixture of NOp and O2 in acid as the nitrosating agent and reported poor yields of products and increased occurrence of side reactions.

Other Work

Several other instances of the reaction of tertiary amines with nitrosating agents have been reported. T. H. Reade and collaborators published a series of papers (20) on the reactions of substituted dialkyl anilines. They showed conclusively that a t least some of the products must arise from nitrosatine cleavage of the tertiary amine and they demonstrated the nature of the organic products as indicated in reaction (4). p-P-CrH4S(CH&

+ HNO?

-

p-R-C6H,S(CH3)N0

+ CHzO

(4)

The reaction is particularly successful along this path if the readily nitrosated para position of the ring is blocked. Reade seems to have been unaware of the related work on aliphatic amines. He believed that this reaction was peculiar to aniline derivatives. Although this work was based on earlier observations ( $ I ) , is discussed in modern publications (2$), and has been suggested as a preparative method for nuclear substituted monoalkylated anilines (B),no organic text in common use mentions the reaction. All of them point out that aromatic tertiary amines, in contrast to aliphatic ones, do react with nitrous acid hut only to give nuclear substitution products. Other nitrosating agents can also bring about this

reaction. Cohen and Calvert (24) reported the formation of the p-nitroso-N-methyl-N-nitrosoaniline on treatment of N,N-dimethylaniline with a compound obtained by the action of nitrous acid on benzyl alcohol. Their unknown compound may have been benzyl nitrite. More to the point, Sitka and Rolfes (25) obtained N-nitroso-N-methylcyclohexylamine on treatment of N,N-dirnethylcyclohexylamine with nitrosyl chloride a t zero degrees in dry ether. They did not isolate any other product but reported that the reaction mixture had an odor of formaldehyde. Finally, the reaction of hexamethylenetetramine with nitrous acid yields products indicative of the same type of reaction ($6). Recent Observations

The last two decades have resulted in few examples of the successful nitrosation of tertiary arnines. Some of the older textbooks, popular before World War 11, mention the reaction very briefly, but the newest ones shun it with only one exception. It was not surprising that the reaction was again "discovered." The characteristic cleavage was first observed by Pars (27) during attempted nitrosations of substituted hydrazines, and then the general nature of the reaction was elucidated by Smith and Pars (28). With a modern appreciation of reaction mechanisms it was possible to develop a reasonable explanation for the reaction path as well as to indicate why the reaction could have had such a checkered career. Smith and Pars (28) propose that the nitrosation of tertiary amines involves electrophilic attack on amine nitrogen followed by 1,2 elimination to give an irnrninium compound which is hydrolyzed to t,he final products.

The N-nitroso derivative of the secondary amine, the observed reaction product, would result from nitrosation of the secondary amine after hydrolysis of the irnminium intermediate. This path is analogous to several other reactions of amines: the action of bromine on tertiary amines as well as the degradation of amine oxides in acid or by means of sulfur dioxide can be similarly formulated (28). The other nitrogenous product, nitroxyl, HNO, is known as an elimination product from a number of similar organic reactions where C-NO or %NO bonds are broken (29). Like most electrophilic attacks on amino nitrogen, the reaction is pH dependent. The free amine is reactive, the ammonium salt is, a t best, many powers of ten less reactive. Thus, when nitrous acid was brought in contact with tertiary amines in fairly concentrated acid solutions (pH less than 3), no reaction was observed in cold dilute solutions. However, a t higher pH ranges (pH 3 to 6), especially at elevated temperatures or in concentrated nitrite solutions, the nitrosative decomposition can be observed. From the recorded examples it is clear that all the 'Lsuccessful" work was performed under one or more of the latter conditions. Guether (5) carefully neutralized both amine salt and nitrite solutions, Kishner (8) stresses' that the reaction takes place in weak acid, and others had worked with excess nitrite ion. Volume 40, Number 4, April 1963

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Mechanism

the old concept has vanished and long after the facts have made it untenable. No doubt the lack of recognition of this reaction has prevented its full use from being developed. As has been suggested previously, the decomposition of alkaloids by means of nitrous acid ought to he a useful reaction. The conditions are much milder than most other such degradative schemes. The very limited use probably results in part because of lack of knowledge concerning the proper experimental conditions. By use of acetate buffers the reaction can be carried out under rather mild conditions. Only recently has any attempt been made (31)to extend some qualitative observations by Wegler and Frank (18) that the ease of splitting of alkyl groups is henzyl > alkyl > cyclic. I t is time that a reaction with so much supporting evidence be recognized generally so that it need not be "discovered" again in another decade!

The first balanced equation for this reaction was the one written by Icishner (8) (see equation 1 above). This was adopted by Karrer in his text (SO),although aldehydes have often been reported as products and there is no evidence that alcohols are ever formed. Perhaps this equation was favored because it permits a simple stoichiometric relationship. Any mechanism involving an oxidation of an alkyl residue as an integral part of the reaction requires more complicated stoichiometry and raises a question concerning the fate of the nitrogen species which causes the oxidation. At present the detailed path is being investigated (31). There is every reason to believe that the path for nitrosation of tertiary amines is, a t least in the initial stages, similar to the reaction path for primary or secondary amines with the same reagent. In each case it is assumed that the unprotonated amine reacts, using the unshared electron pair, with an electron deficient nitrogen bearing species R,N:

+ NO

+

-

IR,N-NOl

Literature Cited ( 1 ) BUTTERFIELD, H., "The Origins of Modern Science," G. Bell and Sons, Ltd., London, 1958, p. 2. W., Ann., 138,319 (1866). ( 2 ) HEINTZ, ( 3 ) GuETHER,Arehi". P h a m . , 2,123,200 (1864 1. ( 4 ) GRIGNARD, V., DUPONT,G., AND LOEGUIN, R. ''Trait6 de Chimie Organiqi~e,"Val. XII, 1941, p. 90. (E) L~::nz:x~, II., .?zI., I!?, ?LIZ :? J?:. ( 6 ) ROHDE, W . , A n n . , 151,366(1869). P. "Lehrbuch der Organischen ( 7 ) MEYER,V. AND JACOBSON, . Chemie,"Znded. Vol. 1, 1 9 0 7 , ~345. N., Bull. soe. ehim. France, 16,1289 (1896). ( 8 ) KISHNER, E., Ann.. 267,254(1892). ( 9 ) SCHMIDT. ( 1 0 ) Forlschritte der Teerfarbenfabrikation und verwandter Indusbierweige, 14,348 (1924); Chcm. Zent., 1925,293. E., AND WALTHER, L., Bw., 63,8.52(1930). ( 1 1 ) SPEYER, , J . P h a n . Soe. Japan,49,91(1929). ( 1 2 ) O c ~ l a lE., N . K., AND YUNOSOV, S. V., J . Gen. Cheei., ( 1 3 ) ABTTBAKIROV, U.S.S.R.,24,733 (1954). ( 1 4 ) COOKBON, R. C., AND TREVITT,M. E., J. Chefs.Soc., 1956, 2689. ~-~~ ( 1 5 ) JACOBS, W. A,, AND CRAIG,L. C., J . B i d . Chem., 136,303. -37.1 - - 1 1-94n) .- ,. GOODSON, J. A,, AND HENRY,T. A,, J . Chem. Soe., 127, 1640 (1925). CHATTERJEE, A,, ANL GHOSAL, S . , N a t u m ~ 8 .47,234 , (19601. WEQLER, R., ANDFRANK, W., Ber., 69,2071 (1936). Ibzd., 70,1279(1937). AITKEN,M. F., AND READE,T . H., J. Chem SOC,1926, G . J. G., ANDREADE, T.H., J . Chem. Soc., 1896; MILTON, 1936, 1749; CROWLEY, G. P., MILTON, G. J. G., READE, T. H., AND TODD, W. M., J . Chem. Soe., 1940,1286. WURSTER, E. ANDKOCH, E., Em., 20,2459 (1887). INGOLD,C. K . , "Structure and Mechanism in Organic Chemistry" Cornell University Press. Ithacn. N . Y., 1953, p. 288. ( 2 3 ) EMERSON, W. S., J . A m . Chem. Soc., 63,2023 (1941). J. B.. A N D CALVERT. H. T.. J . Chem. Soe.. 7 3 . 163 1241 COHEN.

+

The intermediate first formed then stabilizes itself in some way, usually involving loss of a proton if one or more R groups is equal to hydrogen. ,...,....,,.,,

--

.,....,,,",~...~,~.. .....,..... R.N-NO + H'

RINH--NO+

RNH,+-NO-E '

,.,..,.L.

[RNH-NO]

--

(nitrosamine)

[RN=NOHI [RNP'I

-

etc.

The significance of the similarity of mechanism for these three classes of amines is that the unprotonated nucleophilic amine is considered to be the active reagent and that the intial step involves an addition to the amine of an electrophilic reagent. Several texts not only ignore the reaction of tertiary amines with nitrous acid; they go further and suggest reasons why the reaction fails. They claim that the reaction fails with tertiary amines because these have no hydrogen which can be displaced by the nitrosating agent. Statements like the above imply a concerted mechanism involving electrophilic displacement on nitrogen, a rather unlikely prospect in acidic solutions.

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Conclusions

The suggested explanations for the inertness of tertiary amines towards nitrous acid represent the final step in the failure of this reaction to he accepted in the general literature. Somehow, the recorded ohservations have never penetrated the maze of generally accepted information although the reaction should be expected in the light of current mechanistic considerations. True, the reaction proceeds only under limited conditions, but so do most processes. It is interesting to speculate on the tenacity of the mistaken belief in the face of the mechanistic knowledge which predicts that the reaction should be ohserved. Here is a case where the new knowledge still has to force out an old belief long after the utility of

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,

( 2 5 ) SITKA,A,, AND ROLFES,H., B ~ T 53, . , 1243 (1920) W. E.,AND DENO,N. C., J . Am. Chem. Soc., ( 2 6 ) BACHMANN, 7. . 3,7777110.61 - . . . .,- - ,1, (271 PARS,H . G., PhD thesis, U. of Midigan, 1958. ( 2 8 ) SMITH,P. A. S., AND PARS,H. G., J . OW. Chern., 24, 1325 (1959). ( 2 9 ) HEIN,G. E., PhD thesis, U. of Michigan, 1959. ( 3 0 ) KARRER,P., "Orgsnic Chemistry" (English trans.), 4th ed., Elsevier Publishing Co., Amsterdam, 1950, p. 126. R. N., private oommunica( 3 1 ) SMITH,P. A. S.. AND LOEPPKY, tion. \

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