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828 CHAPTER 18 • THE OF ARYL HALIDES, VINYLIC HALIDES, AND . TRANSITION-METAL

Because an aryl cation is forced to assume a nonoptimal geometry and hybridization, it has a very high energy. The electron-withdrawing polar effect of the ring double bonds also desta-

bilizes an aryl cation, just as a double bond destabilizes a vinylic cation. Thus, SN1 reactions of aryl halides do not occur because they would require the formation of interme- diates—aryl cations—with very high energy. Note that an aryl cation is quite different from the cation formed in electrophilic aromatic substitu- tion (Eq. 16.9a, p. 753), in which the carbocation intermediate is stabilized by resonance. In an aryl cation, the empty orbital is not part of the ring p-electron system but is orthogonal (at right angles) to it. Hence, this carbocation is not resonance-stabilized. The first direct observation of an aryl cation (the phenyl cation, Eq. 18.10) was reported in 2000 by chemists at the Ruhr-Universität in Bochum, Germany, who trapped the cation at 4 K and ob- served it spectroscopically. Thus, aryl cations are known species. However, they are far too unstable

to form from aryl halides under typical SN1 conditions.

PROBLEM 18.3 Within each series, arrange the compounds according to increasing rates of their reactions by

the SN1–E1 mechanism. Explain your reasoning. (a) Br Br Br

"C A CH2 "CH CH3 "CH CH3 cL 0L L cL L

AB C

(b) Cl Cl

"CH CH3 Br kL L kL

ACB

NUCLEOPHILIC AROMATIC SUBSTITUTION 18.4 REACTIONS OF ARYL HALIDES

Although aryl halides do not undergo nucleophilic substitution reactions by SN1 and SN2 mechanisms, aryl halides that have one or more nitro groups ortho or para to the un- dergo nucleophilic substitution reactions under relatively mild conditions.

67 °C, 10 min O N F K CH O O N OCH K F (18.11) 2 | 3 _ CH OH 2 3 | _ LvL + 3 LvL + p-fluoronitrobenzene p-nitroanisole (93% yield)

NO2 NO2

) 170 °C, 6 h ) O N Cl NH O N NH HCl (18.12) 2 3 (pressure) 2 2 LvL ++32LvL 1-chloro-2,4-dinitrobenzene 2,4-dinitroaniline (70% yield) 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 829

18.4 NUCLEOPHILIC AROMATIC SUBSTITUTION REACTIONS OF ARYL HALIDES 829

These reactions are examples of nucleophilic aromatic substitution: substitution that occurs at a of an aromatic ring by a nucleophilic mechanism.

Let’s examine some of the characteristics of this mechanism. Like SN2 reactions, nucle- ophilic aromatic substitution reactions involve and leaving groups, and they also obey second-order rate laws.

rate k[aryl halide][] (18.13) = However, nucleophilic aromatic substitution reactions do not involve a concerted backside substitution for the reasons given in Sec. 18.1. Two clues about the come from the reactivities of different aryl halides. First, the reaction is faster when there are more nitro groups ortho and para to the halogen :

NO2 NO2 relative rate ) ) 5 6 (18.14a) O2N Cl_OCH3 O2N OCH3 Cl_ 10 –10 LvL + LvL +

(18.14b) O2N Cl _OCH3 O2N OCH3 Cl_ 1 LvL + LLv +

≈0 (18.14c) Cl _OCH3 no reaction vL +

Second, the effect of the halogen on the rate of this type of reaction is quite different from that

in the SN1 or SN2 reaction of halides. In nucleophilic aromatic substitution reactions, aryl fluorides are most reactive. Reactivities of aryl halides:

Ar F Ar Cl ' Ar Br ' Ar I (18.15) L >> L L L In SN2 and SN1 reactions of alkyl halides, the reactivity order is exactly the reverse: alkyl flu- orides are the least reactive alkyl halides (Secs. 9.4F and 9.6C). These data are consistent with a reaction mechanism in which the nucleophile reacts at the halide-bearing carbon below (or above) the plane of the aromatic ring to yield a resonance- stabilized anion called a Meisenheimer complex. In this anion, the negative charge is delocal- ized throughout the p-electron system of the ring. Formation of this anion is the rate-limiting step in many nucleophilic aromatic substitution reactions.

_OCH3 3 12 rate-limiting O2N F LvL

_ OCH3 OCH3 OCH3 12 12 12 O2N 2 % O2N _ % O2N % (18.16a) L/ Ll Ln ΄ "F 3 "F "F ΄ 1 a Meisenheimer complex _ 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 830

830 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

The negative charge in this complex is also delocalized into the nitro group. M O OCH _O OCH 3 1 3 3 12 3 #N N A _ % % (18.16b) | Ll3 "F | l "F ΄_OM _OM ΄ 3 21 3 12 The Meisenheimer complex breaks down to products by loss of the halide .

_ OCH 4 3 O N OCH F _ (18.16c) O2N % 2 3 L/ "F LvL + 3 12 3 12 3 Let’s see how this mechanism fits the experimental facts. Ortho and para nitro groups accelerate the reaction because the rate-limiting resembles the Meisenheimer complex, and ortho and para nitro groups (but not meta nitro groups) stabilize this complex by resonance. Fluorine also stabilizes the negative charge by its electron-withdrawing polar ef- fect, which is greater than the polar effect of the other . Because the loss of halide is not rate-limiting, the basicity of the halide, or equivalently, the strength of the carbon–halogen bond, is not important in determining the . Although we have used aryl halides substituted with ortho- and para-nitro groups to illustrate nucleophilic aromatic substitution, it stands to reason that other that can provide resonance stabilization to the Meisenheimer complex can also activate nucleophilic aromatic substitution. (See, for example, Problem 18.5a.)

Notice how the nucleophilic aromatic differs from the SN2reactionof alkyl halides. First, there is an actual intermediate in the nucleophilic aromatic substitution re- action—the Meisenheimer complex. (In some cases, this is sufficiently stable that it can be di-

rectly observed.) There is no evidence for an intermediate in any SN2reaction.Second,thenu- cleophilic aromatic substitution reaction is a frontside substitution; it requires no inversion of

configuration. The SN2reactionofanalkylhalide,incontrast,isabacksidesubstitutionwith STUDY GUIDE LINK 18.1 inversion of configuration. Finally, the effect of the halogen on the reaction rate (Eq. 18.15) is Contrast of Aromatic Substitution different in the two reactions. Aryl fluorides react most rapidly in nucleophilic aromatic sub- Reactions stitution, whereas alkyl fluorides react most slowly in SN2 reactions.

PROBLEMS 18.4 Complete the following reactions. (No reaction may be the correct response.) (a) heat O2N Cl C2H5NH2 LcL + 2

$NO2 (b) F CH (CH ) S 3 2 3 _ CH OH cL + 12 3 3

$NO2 (c) 25 C CH O F CH O ° 3 3 _ CH OH LcL + 21 3 3 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 831

18.5 INTRODUCTION TO TRANSITION-METAL CATALYZED REACTIONS 831

18.5 Which of the two compounds in each of the following sets should react more rapidly in a nu-

cleophilic aromatic substitution reaction with CH3O_ in CH3OH? Explain your answers. (a) F F (b) F F NO NO " 2 " 2 " " M or M or r r r r %NO2 "C "NO2 O OCH ( % 3

INTRODUCTION TO TRANSITION-METAL 18.5 CATALYZED REACTIONS

We’ve just learned that SN1 and SN2 reactions cannot be carried out on either aryl or vinylic halides. However, reactions that look very much like nucleophilic substitutions can be carried out using certain transition-metal catalysts. Here are some examples.

H3C $ Pd P L Lc 34 CH3 (catalyst) CH3 (CH3CH2)3N % H2C A CH2 % HBr (18.17) CH C' N () i + 3 i + neutralized by Br 18 h, 125 °C CH A CH2 % % the (CH3CH2)3N o-bromotoluene o-methylstyrene (86% yield) This reaction, called the Heck reaction, has become very important in organic synthesis. We’ll revisit this reaction in Sec. 18.6A. Notice the formation of the carbon–carbon bond and the re- lease of bromide as HBr. Superficially, it looks as if the conjugate-base anion of ethylene dis- places bromide ion from the aromatic ring. However, this reaction occurs by a very different mechanism and does not happen without the palladium catalyst. (Only about 1 mole % of the catalyst is required.) In the following reaction, we see the substitution of a vinylic bromide by a thiolate anion.

Ph Br Ph SCH2CH3 Pd(PPh3)4 (catalyst) CCA Li SCH CH CCA Li Br (18.18) $ ) | _ 2 3 $ ) | _ + + HH) $ HH) $ (93% yield) This reaction, too, looks superficially like a nucleophilic substitution reaction. But this reac- tion also proceeds by a different mechanism and does not take place without the catalyst, which is present in only 1 mole %. Notice also the retention of , a very

different result from that expected in an SN2 reaction. These are but two examples of thousands now known in which transition-metal catalysts bring about seemingly “impossible” reactions. The field of transition-metal catalysis has ex- ploded in the last four decades, and it has become very important in both laboratory and indus- trial chemistry, as well as in some areas of biology. This field is part of the larger field of