a
NUCLEOPHILIC SUBSTITUTION IN AROMATIC SYSTEMS RICHARD G. GILLIS Royal Melbourne Technical College, Victoria, Australia
nucleophilic substitutious have not had nearly as much attention as they deserve in comparison with electrophilic substitutions in aromatic systems, and with both kinds of substitution in aliphatic compounds. Now that undergraduates are more generally being taught something of structure and electronic mechanisms, it seems worth while to classify and sum-. marize those important aromatic nucleophilic reactions with which they should become acquainted, placing emphasis on those of special importance in general laboratory practice and in commercial operations. Such a summary is attempted in this review, without going deeply into details of mechanism. For these, and for further examples, reference should be made to the extensive report of Bunnett and Zahler (I) and the critical discussion by Ingold ( 2 ) . We shall define aromatic nucleo~hilicsubstitutions as those reactions in which a ~ewiHbase (nucleophile, electrodotic reagent) replaces hydrogen or some other group directly attached to an aromatic system, with or without rearrangement.' In general these reactions may be formulated thus: AROMATIC
=-x
+ :N
- 0-N +
Replacement of Groups Normtally Stable as Anions, Without Activation of the Ring. Some important commercial reactions fall into this class: One is the Dow process for the manufacture of phenol from chlorobenzene (4) :
Another is the related ammonolysis of chlorohenzene to aniline (5):
The formation of diphenyl oxide and diphenylamine as by-products is strong evidence for the mechanism. They can be seen to be the result of a second stage of the same Process. -
+ :GI-
:X
CI
:HnN
NH
the nucleophile :N attacking the ring a t a point of elecI tron deficiency. Substituents which accentuate this deficiency will in general facilitate the reaction. The normal rules for electrophilic substitution such as the Hammick-Illingworth rule are reversed, and powerful The formation of aniline from phenol has been the Subactivation in the para and ortho positions is caused by ject of patent application (6),as has the formation of -onium groups (especially diazonium), nitro, nitroso, diphenylamine from phenol and aniline (7). These recyano, carboxyl, carbony4 and sulfone groups in partic- actions all require high temperatures to give ular. However, there are cases of nucleophilic sub- yields (200400°C.); the same type of reaction can be stitution without the help of such activating groups, carried out at much lower temperatures when suitable and also some anomalous orientations. Mostly these activating substitnents are present. reactions are of the S N type ~ (bimolecular) but some Also requiring severe experimental conditions are the are almost certainly S N (unimoIecu1ar); ~ others have reactions of aromatic sulfonates in fusions, e. g,, the cyclic intermediates but can still he classed as nucle- formation of sodium phenate from sodium benzeneophilic. The main types are here arranged into six sulfonate and sodium hydroxide. categories, according to the group replaced. This has been found a suitable approach in undergraduate =-SOa+ :XSOa-teaching. 1" this ~ u b c l aX ~ ~may , be OH, SH, CN, and NHs and 1 ~h~ entire aromatic ring is taken as the origin or focus of attention rather than some particular atom. One might equally important examples exist in the naphthalene and anthrawell say that the ring makes a n electrophilic attack on the Lewis quinone as well as the benzene series. base, hut unless a convention is adopted and adhered to, confu~h~ ~~~h~~~~reaction (q is a nnc.eophilic sion roiU result. Brown and co-worker8 have recently used the tution in which activation by substitueuts is not essen~ ~ - ~ ~ ~ f t ~ opposite paint of view in classifying the ~ ~ i ~ dreaction tial: ss a nucleophilio mbstitution (3).
- OX +
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298
in electrophilic substitution, the iodoxy group should be para activating for nucleophilic substitution; however, p-nitroiodoxybenzene with azide ion has been shown to give p-nitrophenylazide rather than p-iodoxyphenyhzide (18).
thesis of Chloroquin, Atebrin, and similarly constituted antimalarials. OH
CI
NH-R I
A positive pole directly attached to an aromatic ring is powerfully deactivating and meta directing for electrophilic substitution. I t should be para-ortho activating for nucleophilic substitutions and such is the case, the most important example being the diazoninm ion. Electrophilic substitution is rarely observed in aromatic diazonium ions since the deactivation of the ring requires experimental conditions which are usually too severe for the relatively unstable ion to survive. However, nucleophilic substitutions, both para and ortho, do occur. Reactions of the type:
have been observed and should be anticipated as a possible cause of embarrassment in preparative work; their scope is summarized by Saunders (19). Replacement of an ortho substituent also is not uncommon, especially by hydroxyl, as further loss of a proton gives the very stable diaw oxide. N
Replacement of Hydrogen Which Appears as Hydride Ion. Since hydride ion is stable only in nonaqueous media, examples of reactions in this class are less common than in the first two classes. The most important is the Chichibabin reaction (B),the amination of heterocycles with alkali amides. In pyridine the orientation is unusual, though not anomalous: the a position is preferred to 7 and further substitution occurs a t a' giving 2,6-diaminopyridine. A very unusual case in which activation is by the carbony1 group is that reported by Fuson and Tull (29); steric effects from the duryl group may be important in this example.
N
Replacement of Hydrogen as Hydride Ion Followed by Oxidation to Proton. Hydrogen may be replaced by a I I I NO* NO* NO, nucleophile in aqueous media if the hydride ion can be immediately oxidized. Suitable mild oxidants have Several summaries of this type of reaction have been been atmospheric oxygen or potassium ferricyanide in made without the mechanism's being recognized ($0). the alkaline conversion of mdinitrobenzene to 2,4diniThe diazonium ion (11) has recently been shown t o give trophenol, and of sym.-trinitrobenzene to picric acid. a variety of nucleophilic substitutions according to Similarly, trinitrobenzene can be converted to picraconditions (21). mide by hydroxylamine which acts as its own oxidizing agent (24). An apparently related reaction is the conversion of mdinitrobenzene to 2-nitro-6-methoxybenzonitrile by the action of potassium cyanide in methanol (17). Since the yield is low (22 per cent) the mechanism may not be clearcut. I
The deactivation by the ring nitrogen of pyridinetype rings toward electrophilic reactions is reflected in the activation of the a and 7 positions for nucleophilic substitutions. Many of these take place in an acidic environment so that the pyridinium ion is the effective activator. Adequate examples are found in the syn-
NO~Q
-xo2
A KCN
CHIOH
OpNoz
CH*O--/
An example from an important dyestuff synthesis is the oxidative alkali fusion of anthraquinone-2-sulfonic acid leading to alizarin.
JUNE,1955
@bPoH 0
OH
~
r
~
r
~
NO* \
o$-SOaNa
o~ "o 0 ~~ 0~ CHaONa
-A
Y
Y 0
8
C-COOC&
0
Nucleophilic Substitution Accompanied by Rearrangement. Two fairly well known rearrangements which are essentially nncleophilic substitutions are the Smiles rearrangement (25) of which the following is an example :
C-COOCHs
II
'0
\ NO2
and the von Richter reaction (26) . . which is illustrated by a simple typical case: Br
Br
I
Another example of the same reaction is that 2,4-dinitrophenylacetone under similar conditions gives 3acetyl-6-nitrobenzisoxazole (29). A second type of uucleophilic ring closure is the synthesis of oxindole recently reported by Neil1 (50). Al-
I
NO?
The rearrangement of pheuylhydroxylamine to paminophenol has recently been recognized as an intermolecular nucleophilic substitution rather than a simple intramolecular rearrangement by Heller, Hughes, and Ingold (27), who suggest that the course of the reaction is:
A
Y
H
where y is OH or any other available nncleophile; in alcoholic media 0-ethers are observed as products. Nucleophilic Substitution Leading to Ring Closure. Most ring closure reactions occur under acidic conditions and follow an electrophilic course, e. g., the formation of anthraquinone from 0-benzoylbenzoic acid. There are, however, at least two ring closures involving a nucleophilir step, and possibly others have been recorded but are so far unrecognized. The first is the formation of benzisoxallolesin such a sequence as that shown, which was used by McGhie and co-workers (28) in a synthesis of paminosalicylic acid.
though it is not yet clear what are the intermediate stages, one must be nncleophilic. A similar closure leading to a six-membered ring (3,4-dihydrocarbostyril) has also been reported (51). Addendum. A s was mentioned in the introduction, it is not the purpose of this survey to discuss mechanisms in detail. This is adequately done elsewhere. But for those whose interest will lead them to seek recent kinetic studies, the postwar papers of Berliner (52), Bevan (SS), Miller (54), and Sandin (55) will provide useful material Miller has also published a comprehensive summary of the activation t o be expected from various groups in terms of their inductive, mesomeric, and electromeric effects (56).
(1) BUNNETT,J. F., AND R. E. ZAALER,Chem. Revs., 49, 273 (1951). \----,.
(2) INGOLD.C. K., "Structure and Mechanism in Organic Chemistry," Cornell University Press, 1953, Chap. 15. (3) BROWN,H. C., H. W. PEARSALL,L. P. EDDY,W. J. WALLACE, M. GUYSON,AND K. LER. NELSON, Ind. Eng. Chem., 45, 1462 (1953). (4) GROGGIN" P. H., "Unit Processes in Organic Synthesis," 2nd ed., McGraw-Hill Book Co., Inc., New York, 1938, p. 629. (5) bid., p. 346. (6) British Patent 619,877; Chem. Abst~mts,43, 5799e (1949). (7) British Patent 611,316; Chem. Abstnrcts, 43,34545 (1949). ( 8 ) DUKE. N. L.,"Organic Reactions," John Wiley & Sons, Ino., New York, 1942, Vol. 1, p. 106. (9) M,,,,, D, T,,ckm.neos:, 42, 189 (1948), (10) MEISENHEIMER, J., Ann., 323, 205 (1902).
JOURNAL OF CHEMICAL EDUCATION
300 (11) HOPK~N h WILMAMSLTD., RESEARCH STAW, "Organic Reagents for Organic Analysis," Hopkin & Willixms, London, 1944. W. A,, J . Am. Chem. Sac., 74,5118 (1952). (12) SCHROEDER, (13) FIESER,L. F.,A N D M. FIESER,Yhganic Chemistry," D. C. Heath and Co., Boston, 1944, p. 579. O., A ~ a l e ~ a s ogeim. c. argentina, 38, No. 187, 19 (14) GALMARINI, (1950); Chem. Abstracts, 45, 5721 (1953). p. W., T. R. HITCHINOS, A N D G. M. FILL, (15) RORERTSON, J. Chem. Soc., 1950, p. 808. A. A,, ihid., 1952, p. 4368. (16) GOI~BERO, (171 . "Owanic - Svntheses," ~- , RUSSELL. , A,., A N D W. G. TEBBENS. Vol. 22, p. 35. , 70B, 146 (1937) (18) VORGANDER, D., A N D H. D ~ v mBer., K. H., "The A~.omaticDiam Compounds and (151) SAUNDERS, Their Terhnicd Applications," 2nd d . , Arnold, London, 1949, p. 121. N., "Organic Reaotiom," John Ihid., p. 117; KORNRLUM, 1 1944, Vol. 2, p. 274. Wiley h Sons, Inc., New York, 194 BURNESS, D. M. FORT, FIXGER,G. C., F. H. REED,D. Lf. BURNESS, A N D R. R. BLOUGH. B L ~ U G J. JH. ,Am. Chem. Soe.. Soe., 73. 73, 145 (1951). M. T.. T., "Orennir "Orgnnir Reactions.' Reactions," Vol. 1, Chap. 4. LEFFLER, LEIFLER.M. F u s o ~ R. , C., AND 11. TIILL,J . Am. Chenz. Soc., 71, 2543 (1949).
F u s a ~ R. , C., "Advanced Orgnnic Chomistry," John Wiley &Sons, Inc., New York, 1950, p. 308. SMILES, S., ET AL., J . Chmn. Sor., 1931,p.914and~ub~equent papers. vos RICHTER, V., Ber., 4, 21 (18il); RUXNETT,J. F., J. F. A N D F. C. MCICAY,J. 0791. Chena., 15, 481 CORMACK, (1950); BENKESER, It. A , , A N D K. E. BUTING,J. Am. Chem. Soc., 74, 3011 (1952). s , C. I
