CHEM 4113 ORGANIC CHEMISTRY II LECTURE NOTES CHAPTER 16

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1 M 4113 GI MISTY II LTU TS PT romatic lectrophilic Substitution 1 romatic compounds are electron rich species ( 6 -electrons in the aromatic ring). onetheless, they do not undergo standard electrophilic addition similar to alkenes because to do so would permanently disrupt the aromaticity of the ring. owever, aromatic compounds do undergo reaction with certain potent electrophiles, but by an romatic lectrophilic Substitution mechanism. G Y The resonance stabilized cation produced when an electrophile adds to benzene is much more stable than one produced by electrophilic addition to an alkene. owever, it is much less stable than benzene itself. Thus, electrophilic attack on a benzene has a high activation energy, and is therefore rather slow. The benzene reaction is slower because the starting material is so much more stable. Why benzene is much less reactive than alkenes ll romatic lectrophilic Substitution reactions have the same basic three steps: 1. Generation of the electrophilic species. catalyst (usually a powerful Lewis cid such as ll 3 ) is required to generate the electrophilic reacting species. 2. ttack of the -electrons of the aryl ring on the electrophile, with formation of a resonance stabilized cation. This step is reminiscent of electrophilic addition to an alkene. The carbocation intermediate is greatly stabilized by resonance delocalization. onetheless, this is a high energy step because of the disruption of the aromaticity of the ring. 3. Loss of a proton from the cation intermediate at the site of substitution to regenerate an aromatic ring.

2 + 2 + is an electrondefficient species Substitution Product S STBILIZ TI Loss of + from tetrahedral carbon regenerates romaticity orbitals of delocalized intermediate General Mechanism of lectrophilic romatic Substitution ontributing esonance Structures esonance ybrid esonance stabilized arenonium ion. a. Specific xamples of romatic lectrop hilic Substitution Many different substituents can be introduced onto the ring by this process. alogenation, nitration, sulfonation, acylation and alkylation can be carried out with the proper choice of reagents and conditions. 1. alogenation. Br 2, l 2 and I 2 are all, by themselves, unreactive toward aromatic rings, and a promoter or catalyst are required to obtain a suitable reaction. In all three cases, a Lewis cid such as FeBr 3, ll 3 or ul 2 will promote electrophilic addition to the ring. The complexed halogen molecule is then attacked by nucleophilic aromatic ring in a slow, rated determining step.

3 Generation of halogen electrophile 3 Br Br + FeBr 3 Br Br FeBr 3 Lewis ctual reagent - Weakened cid bond between two bromines. atalyst Potent electrophile. Br Br Br FeBr 3 + FeBr 4 - FeBr 3 + Br + atalyst regenerated Br lectrophilic alogenation 2. itration and Sulfonylation. Benzene reacts with concentrated nitric acid ( 3 ) in the presence of sulfuric acid ( 2 S 4 ) catalyst. The electrophile in this reaction is the nitronium ion ( 2 + ), which is generated by protonation of 3 (sulfuric acid is about 10 3 stronger acid) and subsequent loss of water. The nitronium ion adds to the benzene ring to form a carbocation intermediate, which then loses a proton to regenerate the aromatic ring. nother electrophilic substitution reaction of benzene is conversion to a sulfonic acid by a solution of sulfur trioxide (S 3 ) and sulfuric acid (called fuming sulfuric acid). The central sulfur atom of sulfur trioxide is extremely electron defficient and is thus a very potent electrophile. 2 S 4 atalyst 2 itronium ion Potent electrophile dditional esonance Forms lectrophilic itration

4 S 2 S 4 S S Benzene sulfonic acid other resonance structures 4 romatic Sulfonation 3. Friedel-rafts cylation. When benzene reacts with an acid chloride in the presence of a Lewis cid catalyst, such as ll 3, a ketone is formed. In this reaction, an acyl group, -(=), is introduced onto an aromatic ring, hence the term acylation. The electrophile is a carbocation called an acylium ion (or acyl cation), which is formed when the acid chloride reacts with the Lewis cid. Generation of acyl cation electrophile l ll 3 - ll 4 cyl ation - + Intramolecular cylation very useful variation of this reaction involves the intramolecular addition of acid chlorides to benzene rings that a connected to the chain that bears the acid chloride. l Friedel-rafts cylation ll 3 4. Friedel-rafts lkylation. The reaction of an alkyl halide with benzene in the presence of a Lewis cid catalyst gives an alkylbenzene. The electrophile in a Friedel-rafts alkylation is formed by the complexation of the Lewis cid (usually ll3) with the halogen of the alkyl halide in much the same way that the electrophile in the halogenation of benzeneis formed. ither the alkyl halide-lewis cid complex or the carbocation derived from it can serve as the electrophile.

5 Generation of carbonium ion electrophile 5 l ll 3 = lkyl or promary, secondary or tertiary Friedel-rafts lkylation carbonium ion ll 4-3 T: In some cases rearrangements of the initially formed carbonium ion my occur to give isomeric alkylation products lkyl group makes this product morereactive than benzene T: In order to minimize the formation of poly-alkylated products this reaction is usually run using a large excess of benzene, such that the electrophile is more likely to encounter the benzene rather than the initially formed product. 1. Polysubstitution- The product from alkylation is more reactive than the reactant Br ll 3 / 0 less more reactive reactive 2. earrangement- The initial carbocation electrophile will rearrange, if possible, and the rearranged carbocation will lead to the major product ( 3 ) Br + ll 3 / 0 expected product rearranged product 30% 70% 3. eactivity- The ring must be as reactive as a halobenzene Br ll 3 / 0 TI 4. mines- The ring must not contain an amine which will react with the catalyst to form a stable salt which is unreactive. 2 l 3 l 2 ll 3 Limitations of the F- lkylation eaction b. egiochemistry of lectrophilic romatic Substitution on Substituted Benzenes. The 5 ring positions of monosubstituted benzenes are not equally reactive. The ring substituent determines (a) the orientation of the second substituent (either ortho, meta or para) and (b) the reactivity of the ring towards substitution ( and hence the rate of reaction).

6 Substituent Group ame of Group irecting ffect ctivating () eactivating () amino hydroxy alkoxy acylamino alkyl ortho, para ortho, para ortho, para ortho, para ortho, para S I G T I V T I X (X = F,l,Br,I) 2 S 3 halogens acyl carboxy, carboxamido carboalkoxy sulfonic acid ortho, para meta meta meta meta S I G T I V T I cyano meta 2 nitro meta irecting and ctivating Groups in lectrophilic Substitution substituent exerts a directing effect because of kinetic control of the reaction. The intermediate with the lowest energy transition state is formed in the greatest amount (the ammond Postlulate tells us that the TS resembles the intermediate). Thus we can evaluate the relative energies of the various intermediates (i.e. o,p vs m) and predict that the ones with the lowest energy will be formed in the greatest yields. 1., P ITS. n electron donating group (G) will stabilize the intermediate which gives a + charge directly at the ring carbon to which the G group is attached. Thus electron donors are o,p directors because substitution at the ortho or para position will lead to an intermediate with a + charge at the G position. lectron donating groups are (a) those with an unshared pair of electrons on the atom bonded to the ring, which can be delocalized into the ring; or, (b) those without an unshared pair which are electron donating by induction or hyperconjugation. Because o,p directors help to stabilize the + charge formed by electrophilic addition, they are activating, that is they will react faster than benzene. The one exception is seen with the halogens, which are o,p-directors but deactivating. 2. MT ITS. n electron withdrawing group (WG) will destabilize the intermediate which gives a + charge directly at the ring carbon to which the WG is attached.

7 This will result in meta substitution, since the intermediate for meta substitution will not have a + charge at the ring carbon bearing the WG. Because all meta directors destabilize the + charge of the intermediate, they are without exception deactivating, that is they all react more slowly than benzene G (onor Group) is a group that can stabilize a positive charge. This includes atoms that can supply electrons via resonance (oxygen, nitrogen, sulfur). It also includes alkyl and aryl groups that are inductively electron-releasing. T SUBSTITUTI G + G G G G 7 P SUBSTITUTI rtho Substitution allows the onor Group (G) to provide an additional measure of stability via the resonance structure G G G G G Substitution para to thedonor group also gives four important resonance forms. (Form -8 being the form that takes advantage of the lone-pair electrons or the donor group.) MT SUBSTITUTI G G G G Substitution meta to the donor group gives three of the standard resonance forms, but in no case can the lone-pair of the donor group be involved in any form of stabilization. lectrophilic romatic Substitution of onor Substituted renes

8 G G G G ddition of an electrophile to a onor substituted benzene can lead to three different products: ortho, meta and para. Substitution ortho or para to the onor group result in intermediates with additional resonance stabilization that substitution at the meta position does not have. s a result, the ortho and para substitution products are formed at a faster rate than meta and they predominate in the product mixture. owever, any onor Substituted arene will react faster than benzene; even at the meta position. 8 G Y Meta substitution has a higher energy intermediate due to less resonance stabilization rtho, Para substitution leads to a more stable, lower energy intermediate reaction coordinate irecting ffects of onor Substituents on lectrophilic Substitution c. lectrophilic romatic Substitution on isubstituted Benzenes. Further electrophilic substitution of a disubstituted benzene is governed by the same resonance and inductive effects discussed for monosubstitution. owever, it is now necessary to consider the additive effects of the two different substituents present. The following are rules for predicting the orientation of incomming groups in disubstituted benzenes. 1. If the groups reinforce one another, the orientation can be predicted by either group. 2. If an o,p-director and m-director are not reinforcing, the o,p-director controls the orientation. The incomming group goes mainly ortho to the m-director 3. s trongly activating group competing with a weakly activating group controls the orientation. 4. When two weakly activating or deactivating groups, or two strongly activating or deactivating groups compete, substantial amounts of both isomers are obtained; there is little preference. 5. Very little substitution occurs in the sterically hindered position between meta substituents. 6. Very little substitution occursin the sterically hindered position ortho to a bulky o,pdirector such as a t-butyl group.

9 Br 2 FeBr 3 + Br 2 FeBr 3 3 major product rule minor product (very little) rule 5 3 l 2 only product rule 1 l l Br FeBr weak 2 major product rule 2 Br 2 rule 3 FeBr strong rientation ffects in isubstituted Benzenes d. rganic Synthesis Using lectrophilic romatic Substitution. When proposing synthesis that are based upon electrophilic aromatic substitution, it is important to introduce the target substituents in an order such that their activating/directing tendencies are synergistic rather than opposed. In the synthesis of disubstituted benzenes, the first substituent present determines the incoming second. The order of introducing substituents must be carefully planned to yield the desired product 1. If two substituents are o,p-director and m-director and they have an ortho or para orientation, it is necessary to introdue the o,p-director first. 2. If two substituents are o,p-director and m-director and they have and they have a meta orientation, add the m-director first. 3. If the two substituents are meta directors and they have an ortho or para orientation, one of the meta directors has been formed from an ortho, para directing substituent. 4. If the two substituents are o,p-directors and they have a meta orientation, one of the substituents has been formed from a meta director.

10 l 3 3 l 3 ll 3 2 S 4 ll 3 2 S 4 l 2 ll 3 2 Incorrect rder- adding the 2 group first would result in meta orientation l 3 2 S 4 l 2 ll S 4 Incorrect rder - adding the l group first would result in o,p orientation 2 lectrophilic romatic Substitution in Synthesis 2. ucleophilic romatic Substitution (ddition-limination). Simple aryl halides do not undergo nucleophilic substitution by either S1 or S2 processes. For S1 to occur, ionization of the benzene-halogen bond would produce an unstable aryl carbocation; where the empty sp 2 orbital would be perpendicular to the orbitals of the benzene ring. o overlap is possible in such a case, therefore no stabilization occurs. For S2 to occur, backside attack would require the nucleophile to attack from within the ring... this is impossible. X S 1 ionization of -X bond Ionization of -X bond leads to unstable cation Process unlikely. uc X S 2 "Backside" attack Backside attack of nucleophile is prevented uc by steric hindrance Process impossible. Simple ucleophilic Substitution on ryl alides While simple aryl halides are unreactive toward nucleophilic substitutionas described above, certain aryl halides bearing electron-withdrawing groups which are ortho or para to the halide leaving group undergo a special kind of substitution reaction. This reaction is called a nucleophilic aromatic substitution and occurs via an addition-elimination mechanism. lectron-withdrawing groups positioned at the ortho/para positions greatly stabilize the negative charge of the anionic intermediate formed when the nucleophile adds to the -system of the arene. Thus groups such as - 2 and-, which are deactivators toward electrophilic attack, encourage nucleophilic attack. nce the stabilized benzenanion has formed, the aromatic ring is regenerated by loss of a leaving group. alide anions are good leaving groups, although a hydride

11 can be displaced from a suitably substituted benzene. The greater the number of electron-withdrawing groups ortho/para to the leaving group, the more rapid the reaction and less vigorous condition. 11 l l 2 l 2 a 3 ate = 0 a 3 ate = 1 2 a 3 ate = 10 6 TI In electrophilic aromatic substitution, the nitrogroup is the most powerful deactivator, but in nucleophilic aromatic substitution it is the most powerful activating function ucleophilic romatic Substitution 2 l ddition 2 3 l other resonance structures delocalize negative charge onto nitro groups 3 l l - limination 2 2 l l 2 2 Mechanism of ucleophilic romatic Substitution 3. Substitution Involving Benzyne (limination-ddition). second special mechanism for synthesis of substituted benzene occurs in the presence of a strong base. This reaction occurs via the intermediacy of a species which has the benzene ring intact as well as having a "triple bond". It is called Benzyne and is so reactive that it is rapidly converted to products at all temperatures above absolute sero. The mechanism of Benzyne formation is conceptualy similar to alkene formation by 2 processes. With very strong bases,such as amide 2 -, the proton ortho to a halide is abstracted by the base. The pair of electrons from the - bond

12 left behind then form a " -bond" causing the loss of a halide leaving group. The new Benzyne appears to have a triple bond in the ring. The Benzyne can then undergo addition reactions. 12 l 3 limination 3 Benzyne MISM 1 st limination step a 3 TF 2 ddition o specific regiochemistry l 3 2 nd ddition step l -l Substitution via Benzyne Intermediate 3 4. eduction of the romatic ing. Benzene and its derivatives are stabilized by resonance; benzene is very resistant to the catalytic hydrogenation of its double bonds. igh temperatures and pressures of 2, and/or a highly specific transition-metal catalyst are required. uring this process the benzene ring is reduced completely to a cyclohexane ring. It is impossible to stop the catalytic hydrogenation of benzene at the diene or alkene stage.

13 2, Pt/ high temp high pressure 2, Pt/ high temp high pressure 2, Pt/ high temp high pressure 13 VY SLW FST FSTST particularly useful alternative to Pt, Pd and i hydrogenation catalyst is hodium metal deposited on a carbon surface. h/. This allows hydrogenation at low temperatures and one atmosphere pressure of 2. 3 h/ 3 1 atm atalytic ydrogenation of Benzene 3 a. issolving-metal eduction of romatic ings (Birch eduction). romatic rings are difficult to reduce by catalytic hydrogenation, however, they are easy to reduce by a dissolving-metal reduction process (remember the dissolving-metal reducton of alkynes). Treatment of aromatic compounds with either Li or a in a mixed 3 /ethanol solvent leads to the formation of 1,4-cyclohexadiene rings. Thus process is known as the Birch eduction. When a monosubstituted benzene is subjected to Birch eduction, the regiochemistry of the 1,4-diene is determined by the type of substituent present on the ring. lectron donating groups will form 1-substituted-1,4-cyclohexadienes, whereas electron withdrawing groups wil give 3-substituted- 1,4-cyclohexadienes. lectron onating Substituents lectron Withdrawing Substituents egiochemistry of Birch eduction 5. Side hain xidations. The aromatic ring of benzene is very stable to oxidation except under very vigorous conditions. In fact, when an alkyl benzene is oxidized, the alkyl group is oxidized to an acid group, -, while the ring is left intact. The length of the chain does not matter, all carbons except the

14 one directly attached to the ring (which becomes the or -) will be lost. For this reaction to succeed, there must be at least one atom on the attached to the ring KMn , 24 h r 3, 2 S 4 100, 48h 3 Mn or r forcing conditions ( 3 ) 3 o ydrogen Mn or r forcing conditions TI Side hain xidation of lkylbenzenes 6. Benzylic Brominations. The considerable stability afforded to cations, anions or radicals situated on a carbon directly attached to the ring ( i.e. the benzylic position) is a function of the ability of these benzylic intermediates to delocalize charge into the benzene ring through resonance. Thus benzylic carbons are similar to allylic carbons and can undergo similar reactions, in particular they can be selectively brominated through the use of -Bromosucinimide (BS). Benzyl cation,radical or anion (* denotes +, - or ) * * * * 2 Planar array of -orbitals for the delocalized intermediate esonance Structures of Benzyl Intermediates

15 2 2 Br heat, light and/or peroxides l Br 15 Br + Br 2 2 Br benzyl radical-resonance stabilized + Br Br 2 Br + Br 2 + Br Benzylic Bromination with BS