Potassium Amide

KNH2

[17242-52-3]  · H2KN  · Potassium Amide  · (MW 55.13)

(strong base and nucleophile; used for the generation and trapping of arynes; has been used extensively to study the reactivity of heterocyclic systems)

Solubility: 1.7 M in liquid ammonia;1 1.3 × 10-4 M in THF.2

Preparative Methods: a solution of potassium amide in liquid ammonia is prepared by adding pieces of Potassium to liquid Ammonia in an ordinary three-necked flask equipped with a mechanical stirrer.3 A piece of potassium is added to liquid ammonia and after the appearance of a blue color, a few crystals of iron(III) nitrate hydrate are added as catalyst. The remaining pieces of potassium are added at a rate which maintains active hydrogen evolution. Discharge of the deep blue color indicates complete conversion to potassium amide. External cooling is not required since the evaporation of ammonia will provide ample cooling.4 If the reaction must be maintained at -78 °C then a dry ice-acetone condenser is necessary, otherwise an air condenser is sufficient. The resulting opaque mixture contains potassium amide which is mostly in solution. A more elaborate two-flask assembly for the generation and transfer of a potassium amide solution has also been described.5

Handling, Storage, and Precautions: potassium amide is flammable and ignites on contact with moisture. Excess material is destroyed by careful treatment with ethanol or isopropanol. In the preparation of potassium amide the following precautions should be noted. Potassium is a silvery gray metal but it can form an explosive peroxide coating. If it acquires an orange or red color or an appreciable oxide coating it should be considered extremely hazardous. Extreme caution should be exercised in any attempt to isolate potassium amide as it is suspected to be shock sensitive following partial oxidation. An explosion has been reported during the isolation of dry potassium amide.6 Reactions should be performed in a fume hood to prevent exposure to ammonia. Hydrogen is evolved during the generation of potassium amide. No ignition source should be present.

Introduction.

Potassium amide is both a strong base and a strong nucleophile and thus it has been used most effectively in reactions which exploit both of these properties, such as the generation and trapping of arynes, the amination of aromatic systems, and the rearrangement of various heterocyclic systems. Examples of these types of transformations are described below. The reagent has also been used simply as a strong base to induce deprotonation or elimination reactions, provided there are no competing nucleophilic reaction pathways available. This is currently a less important feature of the reagent given the ready availability of strong, nonnucleophilic bases, but a few examples are described at the end of this section.

Aryne Formation.

Potassium amide in liquid ammonia has been used extensively in the generation and trapping of benzynes via dehydrohalogenation of phenyl halides.7 One of the definitive experiments providing evidence for the existence of benzyne involved the treatment of [1-14C]chlorobenzene with potassium amide in liquid ammonia to provide equal amounts of [1-14C]aniline and [2-14C]aniline (eq 1).8 The potassium amide-ammonia system has since been used for the preparation of various substituted anilines.9

Potassium amide has also been utilized extensively for the generation and trapping of various six-membered hetarynes including those generated from halogenated pyridines, diazines, isoquinolines, naphthyridines, and certain multicyclic systems.10 Of the various hetarynes, the evidence supporting the existence of 3,4-pyridyne is recognized as the most convincing. Treatment of either 3- or 4-chloropyridine with potassium amide in liquid ammonia provides a constant ratio of the isomeric amine products (eq 2).11

Although mixtures of amines are usually formed in potassium amide-induced aryne formations, in some cases selectivity for one isomer can be achieved. For example, it was found that treatment of a tricyclic bromobenzo[f]quinoline with potassium amide in liquid ammonia provided only one product via its postulated hetaryne intermediate (eq 3).12 Steric interference by the angular ring is presumed to block formation of the other isomer.

Even in the presence of potassium amide, an intramolecular nucleophile can often compete effectively with amide ion to trap an aryne intermediate, resulting in ring closure. For example, 2-phenylbenzothiazole has been prepared in 90% yield utilizing this strategy (eq 4).13 Intramolecular cyclization onto potassium amide-generated benzyne derivatives has been achieved with carbon, nitrogen, oxygen, and sulfur nucleophiles.14 The strategy has also been successfully used with certain hetarynes, particularly 5-substituted 3,4-pyridynes (eq 5).15 In some cases, however, when potassium amide is used as the aryne-generating base, competitive amination can occur to a significant extent (eq 6).

Potassium amide-generated arynes can also be trapped intramolecularly by a sufficiently nucleophilic phenyl ring. For example, appendage of a negatively charged atom to an aromatic ring can confer sufficient nucleophilicity to the ortho and para positions for this type of reaction.16 An example of this strategy is shown in the synthesis of phenanthridines from haloanils (eq 7).17 In this case, potassium amide is used not only to generate the requisite benzyne but also to activate the system to ring closure via addition of amide ion to the azomethine linkage. For the reaction to succeed, the nucleophilic addition of the amide ion must be very fast relative to the formation of the benzyne. This phenanthridine synthesis tolerates a variety of substituents in the aniline ring, with the exception of hydroxy and nitro groups which are thought to slow the amide addition to the azomethine group significantly.18

Rearrangement of Heterocyclic Systems.

The generation of pyridyne utilizing potassium amide prompted the investigation of the reaction of potassium amide with other heterocyclic azine systems in a search for other hetarynes. However, the halogenated precursors to hetarynes are often more reactive toward nonaryne reactions and in some cases alternative mechanisms for amination are involved. Although it was initially believed that 4-bromo-6-phenylpyrimidine reacted with potassium amide via a 6-substituted 4,5-didehydro intermediate, extensive examinations of the reaction of potassium amide with halopyrimidines led to the elucidation of another mechanism for nucleophilic substitution which proceeds through a ring opened intermediate (eq 8).19 This mechanism is referred to as SN(ANRORC) for addition of the nucleophile, ring opening, and ring closure. The evidence accumulated to support its existence has been reviewed.20 In particular, labeling studies have been used to demonstrate that the amide anion nitrogen becomes incorporated into the ring system (eq 9). This mechanism has been shown to be operative (to a greater or lesser extent) in the reaction of potassium amide with a variety of halogen-substituted heterocyclic systems in addition to pyrimidines, including quinazolines, triazines, and purines. A review of the extensive literature in the area, categorized by ring type, is available.21

Under the conditions of potassium amide in liquid ammonia, many other examples of skeletal rearrangements of heterocyclic systems are known.22 For example, ring contractions have been documented, such as that of 2-chloropyrazine to 2-cyanoimidazole (eq 10).23 In this system, as in many cases, multiple rearrangement pathways lead to multiple products. The details of these potassium amide-induced heterocyclic ring transformation studies are available in a monograph.22a

A particularly useful transformation is the rearrangement of 2-substituted 4-halopyrimidines into s-triazines via a ring-opened intermediate (eq 11).24 This reaction allows for the preparation of unsymmetrically substituted s-triazines which are difficult to obtain by other methods. Competing formation of the 4-aminopyrimidine is minimized by utilizing the chloro derivatives (X = Cl).

Direct Amination of Aromatic Rings.

Potassium amide can be used to induce a direct nucleophilic substitution of amide anion for hydrogen in certain azines.25 Potassium amide in liquid ammonia adds readily to pyrazine, pyrimidine, and pyridazine to give anionic s-adducts which can be oxidized by Potassium Permanganate to give the corresponding aminoaza heterocycle in good yield (eq 12).26 More highly electron deficient systems, like pteridines and nitroaza aromatics, are able to add ammonia itself to give neutral s-adducts which are also oxidized by KMnO4 to heteroarylamines.27 This modified Chichibabin reaction has been reviewed elsewhere.28

Potassium amide can also displace a suitably situated halide on a heteroaromatic ring to provide the aromatic amine, but this reaction is often accompanied by other products from competing rearrangement pathways (eq 10). Simple phenols can be converted to the corresponding aniline in a two-step process involving treatment of the aryl diethyl phosphate ester with potassium amide and potassium metal in liquid ammonia (eq 13).29

Anion Generation.

Potassium amide is a strong base which can be used in simple deprotonation reactions for the generation of various anions. In enolate chemistry, potassium amide in liquid ammonia has been used to generate the dianions of b-diketones and b-ketoaldehydes.30 These species can then be regioselectively alkylated at the g-position. In unsymmetrical b-diketones the second deprotonation occurs at the less substituted g-position (eq 14). The scope of this reaction, including a tabular survey of known examples, has been carefully reviewed.30 Potassium amide in liquid ammonia has also been used for the preparation of 1,3-dinitro-2-keto derivatives from the reaction of cycloalkanones with alkyl nitrates.31

Deprotonation of benzyl ethers by potassium amide in liquid ammonia has been used to effect the Wittig rearrangement.32 In a preparation of phenanthrene, use of potassium amide accomplished the rearrangement to the carbinol in 90% yield after 1 h, whereas Phenyllithium required 1 week (eq 15).33

Examples of large-scale preparations utilizing potassium amide in liquid ammonia for the benzylic deprotonation of lutidine and diphenylacetonitrile have been published.3,34 Allylic deprotonation of 2-chloromethyl-1-butene with potassium amide in THF at 65 °C has been used in an effective preparation of vinylcyclopropane (eq 16).35

Elimination Reactions.

Potassium amide in liquid ammonia can be used as a base to induce elimination reactions.36 For example, this reagent has been used in a preparation of dimethoxycyclopropene via an intramolecular alkylation followed by elimination (eq 17).37 Potassium amide-induced elimination followed by an additional deprotonation has also been used to generate 8,8-dimethylcyclooctatrienyl anion (eq 18).38

Related Reagents.

Lithium Amide; Lithium Diisopropylamide; Potassium 3-Aminopropylamide; Potassium Hexamethyldisilazide; Potassium Diisopropylamide; Sodium Amide.


1. Biehl, E. R.; Stewart, W.; Marks, A.; Reeves, P. C. JOC 1979, 44, 3674.
2. Buncel, E.; Menon, B. JOM 1977, 141, 1.
3. Hauser, C. R.; Dunnavant, W. R. OSC 1963, 4, 962.
4. FF 1967, 1, 907.
5. Bunnett, J. F.; Hrutfiord, B. F.; Williamson, S. M. OSC 1973, 5, 12.
6. Sanders, D. R. Chem. Eng. News 1986, 64 (21), 2.
7. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic: New York, 1967; Chapter 1 and references therein.
8. Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughan, C. W. JACS 1953, 75, 3290.
9. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic: New York, 1967; pp 115-119.
10. Reinecke, M. G. T 1982, 38, 427.
11. Pieterse, M. J.; den Hertog, H. J. RTC 1961, 80, 1376.
12. Reinecke, M. G. T 1982, 38, 485.
13. Hrutford, B. F.; Bunnett, J. F. JACS 1958, 80, 2021.
14. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic: New York, 1967; pp 150-164.
15. Ahmed, I.; Cheeseman, G. W. H.; Jaques, B. T 1979, 35, 1145.
16. Kessar, S. V. ACR 1978, 11, 283.
17. Kessar, S. V.; Gopal, R.; Singh, M. T 1973, 29, 167.
18. Kessar, S. V.; Pal, D.; Singh, M. T 1973, 29, 177.
19. de Valk, J.; van der Plas, H. C. RTC 1971, 90, 1239.
20. van der Plas, H. C. ACR 1978, 11, 462.
21. van der Plas, H. C. T 1985, 41, 237.
22. For examples see: (a) van der Plas, H. C. Ring Transformations of Heterocycles; Academic: New York, 1973; Vol. 2. (b) Rykowski, A.; van der Plas, H. C. JOC 1987, 52, 71. (c) Nagel, A.; van der Plas, H. C.; Geurtsen, G.; van der Kuilen, A. JHC 1979, 16, 305.
23. Lont, P. J.; van der Plas, H. C.; Koudijs, A. RTC 1971, 90, 207.
24. van der Plas, H. C. Ring Transformations of Heterocycles; Academic: New York, 1973; Vol. 2, pp 135-141.
25. The general area of nucleophilic substitution (including KNH2) of hydrogen in azines has been reviewed: Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C. T 1988, 44, 1.
26. Hara, H.; van der Plas, H. C. JHC 1982, 19, 1285.
27. (a) Hara, H.; van der Plas, H. C. JHC 1982, 19, 1527. (b) Wozniak, M.; van der Plas, H. C.; van Veldhuizen, B. JHC 1983, 20, 9.
28. van der Plas, H. C.; Wozniak, M. Croat. Chem. Acta 1986, 59, 33.
29. Rossi, R. A.; Bunnett, J. F. JOC 1972, 37, 3570.
30. Harris, T. M.; Harris, C. M. OR 1969, 17, 155.
31. Feuer, H.; Hall, A. M.; Golden, S.; Reitz, R. L. JOC 1968, 33, 3622.
32. Hauser, C. R.; Kantor, S. W. JACS 1951, 73, 1437.
33. Weinheimer, A. J.; Kantor, S. W.; Hauser, C. R. JOC 1953, 18, 801.
34. Kofron, W. G.; Baclawski, L. M. OSC 1988, 6, 611.
35. Arora, S.; Binger, P.; Köster, R. S 1973, 146.
36. Hauser, C. R.; Skell, P. S.; Bright, R. D.; Renfrow, W. B. JACS 1947, 69, 589.
37. Baucom, K. B.; Butler, G. B. JOC 1972, 37, 1730.
38. Staley, S. W.; Pearl, N. J. JACS 1973, 95, 2731.

Katherine S. Takaki

Bristol-Myers Squibb Co., Wallingford, CT, USA



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