[CONTRIBUTION FROM THE NOYES
LABORATORY, UWIVERSITY
OF ILLINOIS]
MECHANISM OF T H E AMINATION O F HETEROCYCLIC BASES BY METAL AMIDES CLARA L. D E A S Y Received November 16, 1944
Introduction. I n 1914 Chichibabin and Seide (1) discovered that pyridine reacts with sodium amide to form the sodium salt of 2-aminopyridine1 which can be hydrolyzed to the free amine. This type of amination reaction has also been found to occur with other heterocyclic nitrogen compounds and their derivatives and with other metal amides. The scope and limitations of the reaction have recently been comprehensively reviewed (2). The mechanism of the reaction has been assumed to be an initial addition of the metal amide to the -CH=Ngroup (3, 4, 5, 6). This may be followed by an internal rearrangement to the metal derivative of the amine, or decomposition may occur to the amine and sodium hydride, which then interact to give the metal derivative:
It is also postulated that occasionally 1,4-addition may occur, especially if the 2-positions are occupied, giving rise t o the 4-amino ccmpound. While the above mechanism provides an explanation for the entrance of the amino group at the 2- and 4-positions1 it has not proved to be useful in any further interpretation- of the experimental data. Waters (7) and Bergstrom (8) have mentioned briefly that the amination reaction might be regarded as an example of nuclear attack by an anionic reagent. It is the elucidation of the experimental data on the basis of this mechanism which is the subject of this paper. Mechanism of the reaction. Physical data for pyridine have indicated (9) that ionic structures such as the following make significant contributions :
o+
ci
N-
+ N-
..
..
..
Chemical evidence in support of this formulation is abundant. Thus, pyridine does not readily undergo typical aromatic substitution reactions with electrophilic 141
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reagents, and substituents in the 2- or 4-positions do not show typical aromatic behavior (10). On the basis of the above formulation of the structure for pyridine, reactions with nucleophilic reagents would be expected to occur readily a t the 2- and 4positions. The amination of pyridine, then, may be formulated:
The essential points to be noted are that the attack occurs at a carbon atom which has a deficiency of electrons, that the attack is by a nucleophilic group, and that the hydrogen is replaced as negative hydrogen, The questions of the formation of an addition product and of the manner of replacement of the hydrogen of the amino group by the metal atom are ones which are immaterial to an understanding of the course of the reaction. The above mechanism provides an explanation for the introduction of the amino group in the 2- or 4-positions of pyridine. Other heterocyclic nitmgen compounds which have similar residual positive charges on the ring carbons can react with metal amides by the same mechanism. It might be expected, on the basis of the mechanism proposed, that amination would occur with negatively-substituted benzene derivatives, since in these also the ortho and pura carbon atoms have a residual positive charge. This expectation is substantiated in the case of nitrobenzene. When nitrobenzene is gently warmed with sodium amide, the mass becomes incandescent and carbonizes, but the decomposition is extensive; some phenyl isocyanide, but no amino compound, is isolated from the complex mixture of products (11). However, a reaction similar to the amination reaction takes place when nitrobenzene is treated with sodium diphenylamide in liquid ammonia; a 45% yield of p-nitrotriphenylamine is formed, the 4-position being attacked (12). Influence of substituents. If the proposed mechanism is correct, it is t o be expected that meta-directing (negative) groups mill have a favorable influence on the course of the reaction, since they will tend further to withdraw electrons from the ring carbon atoms. Hence the compound will become even more susceptible to attack by the nucleophilic reagent. This is confirmed in the case of certain quinoline derivatives for which the data are available. 2-Carboxyquinoline, 4carboxyquinoline, and 6-carboxyquinoline give yields of 81,70, and SOYc respectively of the amino compounds when treated with potassium amide and potassium nitrate in liquid ammonia at 25" (8), while quinoline, under slightly more favorable conditions (a temperature of 50-TO"), gives only a 53YC yield of 2-aminoquinoline (6). Similarly 2-phenylquinoline gives a 93-100Yc yield of 4-amino-2-phenylquinoline a t 25" (13). On the other hand, ortho-para directing groups would be expected to have a deleterious effect on the course of the reaction if the mechanism advanced for the amination is correct, as they tend.to contribute electrons to the ring. Again the data, which are available for quinoline derivatives only, substantiate the mechanism.
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An amino group in the 2-position of quinoline, or a hydroxyl group in either the 2- or %position, prevents the amination altogether (8). Quinoline is aminated by barium amide in liquid ammonia at 25" to give an 80% yield of 2-aminoquinoline (14), The yield is reduced for each of the following derivatives under the same conditions (8):6-methylquinoline [(?)-amino-6-methylquinolinein 17% yield], 7-methylquinoline (0% yield), 8-methylquinoline [ (?)-amino-8-methylquinoline in 3570 yield], and 6-methoxyquinoline [ (?)-amino-6-methoxyquinoline in 76% yield]. Although no quantitative data are given, it has been observed (15) that it is more difficult t o introduce a second amino group into pyridine than the first. Similarly it is recorded that the amination of a , a'-lutidine with sodium amide is a slow reaction and gives small yields (16). Side reactions. With some compounds which are substituted in the 2-position, the action of the metal amide is t o cause replacement of the group by the amino group. This is the case when a sulfonic acid group or a methoxyl group is present in the 2-position of quinoline (8). This replacement reaction is to be expected on the basis of the above mechanism. The amination reaction proceeds through an elimination as a negative group of the group present on the carbon atom attacked. If the substituent is capable of forming a more stable anion than hydrogen, elimination should take place even more readily (17). In the above examples the groups to be eliminated form the stable anions, SO, and OCH,; and their replacement by an amino group is therefore t o be gxpected. Another side reaction which can occur results in the formation of a secondary amine. For example, in the preparation of 2-aminopyridine from pyridine and sodium amide, a , a'-dipyridylamine has also been isolated (18). The formation of this compound can be explained on the basis of a mechanism similar to the one given for the simple amination:
Again the substitution occurs in the 2- or 4-positions, and not in the 3-position, indicating an attack by a nucleophilic reagent. Catalytic action of potassium nitrate. Potassium nitrate has often been added t o increase the yields in the amination of quinoline, isoquinoline, and their derivatives (6, 19). The amounts added are not catalytic, but are usually, on a molar basis, somewhat greater than the amounts of heterocyclic compounds used. This favorable action can be explained on the basis of the suggested mechanism. The removal of hydrogen as an anion in any cationoid substitution is aided by the presence of an oxidizing agent, since the latter is able to remove the electrons from the negative hydrogen (20). Hence in the amination reaction, nitrate exerts its beneficial action by functioning as an oxidizing agent to facilitate the replacement of H-. The hydrogen is converted to water and the nitrate is reduced to nitrite. The presence of nitrite in the reaction products has been observed experimentally (6). It has also been noted, in the one case
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for which experimental data are available, that when nitrate is used, the amount of hydrogen given off is less than without the nitrate. It has also been shown that other oxidizing agents can function in the same way, though none has been found t o be so effective as the nitrate. Potassium iodate has a slight similar action; potassium iodide has been observed experimentally zw the reduction product. Mercury has also been observed to catalyze to a slight extent the reaction of isoquinoline and of quinoline with alkali amides; an alkali amalgam is the product (6). The mercury probably functions by removing the electron from the negative hydrogen and then forming an amalgam with the alkali ion. This mechanism is supported by the fact that, when quinoline is treated with potassium amide and mercury, the maximum amount of potassium found in the mercury approaches one atom per mole of quinoline used. The amount of hydrogen gas formed simultaneously is about the same as would have been obtained in the absence of the mercury (6). Barium thiocyanate has been observed t o have a favorable action when isoquinoline is treated with barium amide (21). Potassium chlorate, perchlorate, and cyanate, however, mere without action when quinoline was treated with potassium amide in liquid ammonia (6). SUMMARY
The theory that the amination of a heterocyclic base by a metal amide proceeds by an attack of a nucleophilic reagent has been used to account for the experimental data. URBANA, ILL. REFERENCES
(1) CHICHIBABIN AND SEIDE,J . Russ. Phys.-Chem. Soc., 46, 1216 (1914);Chem. Abstr., 9, 1901 (1915). (2) LEFFLER,“Amination of Heterocyclic Bases by Metal Amides.” I n “Organic Reactions,” A d a m , editor, John Wiley and Sons, 1942,Vol. I, p. 91. (3) ZIEGLER AND ZEISER, Ber., 63, 1848 (1930). (4) KIRSSANOW AND IWASTCHENKO, Bull. soc. chim. [5]2,2109 (1935). AND POLIAKOWA, Bull. SOC. chim., [5]3, 1600 (1936). (5) KIRSSANOW (6) BERGSTROM, J . Org. Chem., 2, 411 (1937). (7) WATERS,“Physical Aspects of Organic Chemistry,’? Van Nostrand Co., New York, 1937, p. 455. (8) BERGSTROM, J. Org. Chem., 3, 233 (1938). AND PAULING, J . Am. Chem. Soc., 61, 1769 (1939). (9) SCHOMAKER (10) SIDGWICK, “Organic Chemistry of Nitrogen,” Clarendon Press, Oxford, 1937, pp. 52233. (11) TITHERLEY, J . Chem. Soc., 66, 504 (1894). (12) BERGSTROM, GRANARA, AND ERICKSON, J . Org. Chem., 7, 98 (1942).. (13) BERGSTROM, J . Org. Chem., 3, 424 (1938). (14) BERGSTROM, J . Am. Chem. Soc., 66, 1748 (1934). RIECHERS, RUBENKOENIG, A N D GOODMAN, Ind. Eng. Chem., 32, 173 (1940). (15) SHREVE, (16) CHICHIBABIN, J. Russ. Phys.-Chem. Soc., 47, 835 (1915);Chem. Abstr., 9,2896 (1915). (17) WATERS,Ref. 7, p. 458. (18) WIBAUTAND DINGEMANSE, Rec. trav. chim., 42, 240 (1923). (19) LEFFLER,Ref. 2, p. 96. (20) WATERS, Ref. 7,p. 457. Ann., 616, 34 (1934). (21) BERGSTROM,
