California Association of Chemistry Teachers
Joseph F. Bunnetl University of California Santa Cruz, 95060
The Remarkable Reactivity of Aryl Halides with Nucleophiles
Couper (I) discovered hromobenzene in 1857 and reported that it did not react with silver acetate even at 200°C. Soon thereafter, Riche (2) and Fittig (3) showed both hromo and chlorohenzene to he extraordinarily indifferent also to alcoholic KOH and to ammonia. These halobenzenes came to he regarded almost as liquid sand in their inertness toward what we now call nucleophiles. By 1872, this view had become so firmly entrenched that when Dusart and Bards (4) reported chlorohenzene to react with aqueous NaOH at 3W'C they were greeted with disbelief (5). Even today, textbooks teach that aryl halides are ouite unreactive with nucleo~hilesunless activated by nitro groups, etc. These textbook statements do have- a certain legitimacy; "unactivated" aryl halides are often unreactive under conditions that give facile nucleophilic displacements with alkyl halides. However, under other conditions, which on the whole are profitless to apply to alkyl halides, aryl halides react rapidly with nucleophilic or basic reagents to form products of considerable interest. Sites for Attack
An aryl halide molecule presents several sites for possible attack by reagents of the sort which are called bases, nucleophiles, or electron donors. (These three characteristics are closely allied; many nucleophiles, for example, phenoxide ion, have well-defined reactivity in all three senses.) Five pathways of reaction are suggested by the arrows in the figure and are briefly specified in the legend. Nucleophilic Attack on Carbon Concerted nucleophilic displacement a t aromatic carbon, in the manner of SN2 a t aliphatic carhon, appears not to occur. Available evidence indicates that, when straightforward substitution does occur, the "new" bond between the nucleophile and aromatic carbon must be fully formed before the "old" bond to the nucleofugic group (the leaving group) is broken (6-8). The suhstitution mechanism involves two steps and a sigma complex intermediate in which a negative charge must he accommodated on the other carbons of the ring; see eqn. (1). Suchcomplex is a high energy species, and therefore not readily formed unless there are suhstituents well suited to accommodate the negative charge. The pronounced activating effect of, for example, nitro or diazonio groups ortho or para to the site of nucleophilic attack (6, 7) is thereby intelligible.
This mechanism, now usually symbolized SNAr, is seldom encountered with unactivated awl halides. The few Presented at the 1973 Summer Conference, California Associationof Chemistry Teachers, Asilomar, August, 1973. 312
/ Journal of Chemical Education
cases in which it does operate, despite lack of activation, mostly involve dipolar, aprotic solvents (9, 10) (which enhance the reactivity of nucleophiles (11)) and/or aryl flnorides (12), which generally surpass chlorides, bromides, or iodides in S..A Ireactivitv. Nucleophilic Attack on Hydrogen About 20 years ago, Hall, Piccolini, and Roberts (13) determined the rates of protodedeuteration of several suhstituted deuterobenzenes on reaction with KNHz in liquid ammonia. Reaction occurs according to eqn. (2). They found ortho-fluorine to have an enormous accelerating effect, at least four millionfold. meta-Fluorine was a l s o helpful, hut only one-thousandth as good as ortho-fluorine, and acceleration by para-fluorine was still weaker. These results indicate that ortho-fluorine greatly stahilizes an aryl anion, and there is evidence that the other halogens have similar effects (14, 15). Aryl anion formation is particularly favored when two halogen atoms are ortho to hydrogen (16, 17). D P
The special ease of forming o-halophenyl anions has consequences far beyond the unspectacular reaction of hydrogen isotope exchange. It accounts, for example, for the facility of cleavage of o-halohenzophenones by KNH2 in ammonia (18) (e.g., eqn. (3)) and for the fact that 2,6-dichlo~obenzaldehyde on treatment with aqueous NaOH undergoes not the Cannizzaro reaction hut rather cleavage to m-dichlorobenzene and formate ion (19) (eqn. (4)). Both these cleavage reactions involve initial addition of the nucleophile to carhonyl carhon and subsequent separation of an aryl anion which is finally protonated.
Aryne Formation by Halide Ion Loss from o-Halophenyl Anions Once an o-halophenyl anion has been formed, it may either capture a proton (if available) or lose halide ion to form an aryne (eqn. (5)). Happily, the formation of arynes, their reactions with nucleophiles and their cycloaddition reactions are treated in modern textbooks, and I shall therefore say little more ahout them.
5yy
H
yx-l
H
H
A nucleaphile may attack a halobenzene
(1) at C.1, to replace halogen. (2) at artho-hydrogen to remove it and form an aryl anion which may then (3) expel halide ion to form an aryne. (4) on halogen, to displace an aryl anion, or (5) by stuffing an electron into an antibonding n-orbital to form a radical anion which then disintegrates 10 aryl radical and halide ion.
Inasmuch as o-halophenyl anions do have a proclivity to expel halide ions to form arynes, and inasmuch as much of the chemistry mentioned above and below involves ohalophenyl anion intermediates, I shall however say a few words about what determines the ease of halide ion expulsion, lest the chemistry of o-halophenyl anions seem precarious. First, the ease of halide ion expulsion is I > Br > C1 > F (20). Second, substituents of whatever kind appear to favor proton capture over halide ion loss (21). Third, the solvent has an influence. In solvents such as water which are good proton donors, protonation of an ohdophenyl anion is strongly favored. On the other hand, in dipolar, aprotic solvents such as hexamethylphosphoramide (HMPA), halide ions have high free energy because they are so poorly solvated, and o-halophenyl anions therefore have little tendency to form arynes. Aryne formation tends to occur best in a solvent such as ammonia -not a very good proton donor hut fairly good a t solvating a n i o n s 4 1 when assisted by coordination of the departing halide ion with a lithium or magnesium cation. Nucleophilic Attack on Halogen Nucleophiles may attack halogen atoms attached to good nucleofugic groups, to capture a positive halogen moiety (22-25). If nucleophilic attack on halogen of an aryl halide brings about an actual displacement, the group which is displaced is an aryl anion. Obviously, such a displacement will he facilitated if the aryl anion displaced has ortho-halogen suhstituents. That is, nucleophilic displacement on halogen of an aryl halide occurs more readily when it is ortho to another halogen and most readily when it is flanked in both ortho positions by other halogens. A simple example of such behavior is the dehalogenation of certain oligohalohenzenes which occurs upon warming them with potassium t-butoxide in 50% t-butyl alcohol: 50% dimethylsulfoxide (DMSO) (26); see eqn. (6). A mechanistic study suggests that t-butoxide ion first takes a proton from DMSO, forming the dimsyl anion, CH3SOCH2-, which then attacks the central bromine of 1,2,3-tribromohenzene, capturing a Br+ moiety and displacing a 2,6-dihromophenyl anion. The latter is protonated to form m-dibromohenzene (26).
A more intricate example is the hase-catalyzed halogen dance tri and tetrahalobenzenes. on treat~ ~ ~ (27). ~ , -- ~- , Certain ment with strong bases, notably with ~ o t a s s i u mt-butoxide in DMF or HMPA. undergo " a set of isomerization and disproportionation reactions in which the halogen atoms change their carbon affiliations with seeming abandon.l,2,4Trihromobenzene, for instance, gives di and tetrahromobenzenes as well as its 1,3,5-trihromo isomer; moreover, isotope labelling experiments show that even within the ~
1,2,4-trihromo arrangement the hromine atoms have freely changed places. Such things happen with impressive speed: after ten seconds with t-BuOK in HMPA, the halogen dance has gone about as far as it will, and with remarkably little release of bromide ion (10). Mechanistic studies show that the reversible isomerization of 1,2,4- to 1,3,5-trihromobenzene requires cocatalysis by 1,2,3,5-tetrahromobenzene,and indicate the mechanism of eqns. (7-9). Steps (7) and (9) represent attack of base on hydrogen ortho to bromine to form an o-hromophenyl anion, or the reverse thereof. In step (8) in the forward direction, an aryl anion attacks the 2-bromine of the tetrahromohenzene, capturing a Br+ moiety (to regenerate 1,2,3,5-tetrahromohenzene)and displacing the 2,4,6trihromophenyl anion; the same sort of thing occurs in the reverse direction, with the latter anion attacking either the 1- or the 3-bromine of the tetrabromohenzene. Since the reaction is reversible and attains equilibrium, the mechanism as a whole can he read with equal validity either forwards or backwards.
@
+
:&'
-0-
Br
+
171
.&OH
81
Acceptance of an Electron, and Its Consequences When an aryl halide molecule is forced to accept an electron from a strong electron donor, the electron may enter either an antibonding n-orbital of the aromatic ring or an unfilled atomic olhital, especially of iodine or bromine. In any case, the resulting radical anion is shortlived and decomposes by ejection of halide ion, forming an aryl radical (eqn. (10)). electron donor
+
ArX
-
[ArX].-
-+
Ar.
+
X-
(10)
Several modes of reaction are available to the resulting aryl radical. First, it may abstract a hydrogen atom from a suitable donor. Such a step is involved, for instance, in the radical-induced deiodination of aryl iodides in alkaline methanol (28). The probable mechanism is presented in eqns. (11-14) R.
+
CH,O-
-
RH
+
.CH&
(11)
This is a chain mechanism, with (13) and (14) the propagation steps. In step (13), .CH& (which is the radical anion of formaldehyde) donates an electron to the aryl iodide, and the resulting radical anion decomposes to form an aryl radical. In step (14), the radical abstracts a hydrogen atom from methoxide ion, and the formaldehyde radical anion is regenerated. Second, an aryl radical may accept a further electron to become an aryl anion; the anion is often then protonated to ArH (eqn. (15)). This occurs during electrolytic reduction of aryl halides. The events of eqn. (10) happen at or Volume51. Number5
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1974
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313
near the cathode surface, and are quickly followed by those of eqn. (15). For this reason, the polarographic reduction of an aryl halide normally gives a 2-electron wave 129). electron donor
+
AI.
-
pmton
ArH
A=:-
(15)
of NaOCH3, straightforward substitution occurs to form 4-phenylthioisoquinoline (eqn. (24)), undoubtedly by the SNAr mechanism. Addition of NaOCH3 accelerates formation of this product hut also causes dehromination to isoquinoline (eqn. (25)). However, the effects of NaOCH3 are largely suppressed by addition of azohenzene.
Third, and quite remarkably, the radical may combine with a nucleophile. Such combination is a key step in nucleophilic substitution by the S R ~ mechanism. l This mechanism, recognized for substitutions at saturated carbon in 1966 (30) and a t aromatic sites in 1970 (31), is sketched in eqns. (16-19). electron donor
+
ArX
[ArYI-
+
ArX
-
[ArX].-
[ArXI-
+
+
residue (16)
ArY
(19)
Steps (16) and (17) we have seen before (eqn. (10)). Combination of radical with nucleophile occurs in step (18). The radical anion therehy formed, [ArY].-, is not very stable. One way it can gain stability is by transferring an electron to another AIX molecule (step (19)). Steps (1719) constitute the propagation cycle of a chain mechanism. It is noteworthy that although this cycle involves radical and radical anion intermediates, the net input is ArX + Y- and the net output ArY + X-. In effect, it is a nucleophilic substitution mechanism. Some of the most satisfactorv suhstitutions hv the S ... m~1 mechanism are reactions In hquid ammonia solution stimulated hv the solvated electrons of di*sol\.ed alkali metals. Illustrative examples concern the arylation of amide ion (31) (eqn. (20)), acetone enolate ion (32) (eqn. (21)), and 9-fluorenyl anion (33) (eqn. (22)). Alternatively, reaction (21) occurs under stimulation by light (without need for alkali metal); even a 150-W tungsten lamp external to a Pyrex flask suffices (34). The requisite electrons for initiation (eqn. (16)) are probably somehow obtained from acetone enolate ion through the action of photons.
The influence of NaOCH3 is twofold. First, when radicals somehow are formed, the formaldehyde radical anion is generated (cf. eqns. (11-1211, and it is a superb electron donor. Substitution by the S R N l mechanism is therehy stimulated, to form 4-phenylthioisoquinoline a t accelerated rate. However, methoxide ion is a very good hydrogen atom donor to 4-isoquinolyl radicals (cf. eqn. (14)), and hydrogen atom abstraction leads to isoquinoline. More .CHzO- radicals are therehy formed, to continue the propagation cycles of these coupled radical chain reactions. Azohenzene is a su~eriorelectron acceptor and interferes with electron transfer to the hromd compound, therehy suppressina formation of the 4-isoquinolyl radical. .. Reactions described above show that ''&activated" awl halides react very well in nucleophilic substitutions, if t i e S R N l mechanism is brought into play. Moreover, compounds of the types Ar-O-PO(OCzH5)z and ArN(CH3)~+X-often react as satisfactorily as do aryl halides (32, 37). Inasmuch as these are easily made from phenols and aromatic primary amines, respectively, the synthetic chemist may now reasonably consider phenols and aromatic amines as potential reagents for the arylation of carbanions. ~
Concluding Remarks The chemistry of aryl halides has come a long way since the troubles of Dusart and Bardy in 1872. Most of the progress was made in the past 20 years, and of that most since 1966, and the pace may further quicken. These develonments have manv conseauences: in concents of reaction mechanisms, in new synthetic methods, and in ~otentialitiesfor industrial a ~ ~ l i c a t i o Also. n . . thev. necessitate revision of the sections bn aryl halide chemistry in elementary organic courses, and of the corresponding chapters in textbooks. Acknowledgment I take pleasure in expressing sincere gratitude to my coworkers for their important contributions to the research developments from my laboratory reported above. Much of that research was supported by the National Science Foundation. Literature Cited
Another photo-stimulated S R N lreaction is that of eqn. (23), which effects mesitylation of a carbanion, a rare phenomenon (35).
(11 I21 13) 14) 15)
Coupr,A..J~~f~Liebi88A Chem.. ~ 1 . IU.225118571. Riehe. A.,Ju8lusLiebigsAnn. Chem.. lZI.357(1862): 130.256 118641. Fiftig,R..JusfusLi~bipsAnn.Chsm., 121,361 116621; 133.17 11865). Dusart. L.. sndBsrdy.C., Carnpt. rend. Arod. Sci. Pork. 14.10501L872). Henninger, A,. B e r . 5. 389 11872). Cf., Meyer. K . H.. and Bergiur, F.. Be,., 47.
."
"."",..,.
, , ~ ~ , % O , " ,
161 Bunnetf. J. F..and Zshler. R.E.. Chsm. R e u . 49.273 119511
1131 Hall, G. E.. Pieeolini, R.. and Robem, d . D., J. Amar Cham. Sor., 77. 4540 (19551: see e l m Streiiwieser. A . J r . , and Mams, F.. J. Amer Chem Soc.. 90, ,>mot "-,."-,. C""
(14) Huisgen, R.. Mack. W.. Herbig. K.. Otf. N.. snd Anneser. E.. C h m . E e l , 53. 412
The reaction of 4-bromoisoquinoline with sodium thiophenoxide in methanol (36) is remarkable. In the absence 314
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Journal
of Chemical Education
,,a
