Chapter 16. Chemistry of Benzene: Electrophilic Aromatic Substitution. Reactivity of Benzene

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1 hapter 16 hemistry of Benzene: Electrophilic Aromatic Substitution Reactivity of Benzene - stabilization due to aromaticity makes benzene significantly less reactive than isolated alkenes 2 no reaction KMn 4 no reaction 3, 2 2 /Pt no reaction no reaction - however: 2, Fe 3 benzene bromobenzene (80%) - substitution, not addition product. Why? 1

2 Answer: Addition product would not be aromatic 2, Fe 3 addition or substitution? addition product NT formed substitution product r Electrophilic Aromatic Substitution Mechanism - goes by way of mechanism that permits product to retain aromaticity δ- δ Fe 3 δ- δ 3 Fe weak electrophile strong electrophile - interaction with Fe 3 makes 2 more electrophilic - polarized 2 is then attacked by the π electron system of the nucleophilic benzene ring (rate-limiting step) to yield a nonaromatic carbocation intermediate that is stabilized by resonance carbocation intermediates 2

3 - carbocation intermediate then loses from the bromine-bearing carbon to give a substitution product Fe step is similar to the second step of an E1 reaction - net effect is substitution of with ; aromaticity is retained E E Reaction Progress Usefulness of Reaction S 3 N 2 sulphonation R nitration X alkylation R halogenation acylation Applications: 1) pharmaceuticals 2) dyes 3) precursors for further reactions 3

4 Substitutions Aromatic alogenation - works for and I, F is too reactive with poor yields - electrophile is generated by way of a mechanism similar to bromination 2 Fe 3 catalyst I 2 2u 2 2I 2u I I 2 u 2 I Base I Aromatic Nitration - electrophile is nitronium ion which is generated in a mixture of concentrated nitric and sulfuric acids N 2 S 4 N 2 N - nitro-substituted product can be reduced to yield an arylamine, useful precursors in dye production N 2 N 2 1) Sn2, 3 2) - Aromatic Sulphonation - reaction is effected in fuming sulfuric acid ( 2 S 4 and S 3 ) - electrophile is either S 3 or neutral S 3 S 2 S 4 S S sulphonation is reversible such that it may go forward or backward depending on reaction conditions - useful reaction for production of sulpha drugs for treatment of meningitis and urinary-tract infections 2N S N2 sulfanilamide (antibiotic) 4

5 Problem: ow many products may be formed on chlorination of o-xylene, m-xylene, and p-xylene? Alkylation of Aromatic Rings: The Friedel-rafts Reaction - alkylation, attachment of an alkyl group (e.g. ethyl) to the benzene ring Al electrophile is a carbocation, and results in the direct formation of a carbon-carbon bond - carbocation is generated using aluminum chloride which acts as a catalyst, similar to Fe 3 in the previous halogenation 3 3 Al Al 4-5

6 Mechanism Limitations of the Friedel-rafts Reaction 1) nly alkyl halides can be used; aryl and vinylic halides are unreactive aryl halide vinylic halide 2) If strongly electron-withdrawing groups or amino groups are present on the benzene ring, then poor yields are encountered R X = nitro, amino, carbonyl - limitations hinder usefulness and scope of reaction 3) It is often difficult to stop the reaction once a single substitution has occurred, which leads to multiple substitutions or polyalkylations Al ( 3 ) 3 3 polyalkylation ( 3) 3 ( 3 ) 3 ( 3) 3 major product minor product 6

7 4) arbocation rearrangements (e.g. hydride shift) occur and lead to mixtures of products Al 3,, 0 o sec-butylbenzene (65%) butylbenzene (35%) Acylation - acyl group (-R) is introduced onto a benzene ring by way of a reaction with a carboxylic acid chloride 3 Al 3 80 o 3 - mechanism is similar to that of alkylation; carbocation is stabilized by resonance involving an oxygen atom 3 Al 3 R R - acylations never occur more than once since the product is less reactive than the nonacylated starting material 7

8 Substituent Effects in Substituted Aromatic Rings - what happens if we carry out a reaction on an aromatic ring that already has a substituent? X X X X Result: single product? mixture? no reaction? Two Important Effects 1) Reactivity A substituent affects the reactivity of the aromatic ring Substituents may either activate or deactivate the benzene ring relative to benzene 2) rientation The three possible disubstituted products (i.e. ortho, meta, para) are usually not formed in equal amounts The nature of the substituent already present on the benzene ring determines the position of the second substituent assification of Substituents Three Types of Substituents: 1) ortho- and para- directing activators 2) ortho- and para- directing deactivators 3) meta- directing deactivators 8

9 ontrol of Reactivity and rientation - interplay of inductive effects and resonance effects - inductive effect: - withdrawal or donation of electrons through a σ bond due to electronegativity and the polarity of bonds in functional groups - withdrawal of electrons: δ- δ- δ δ X δ δ- N N - donation of electrons: 3 - resonance effect: - withdrawal or donation of electrons through a π bond due to overlap of a p orbital on the substituent with a p orbital on the aromatic ring - withdrawal of electrons: - effect is greatest at the ortho and para positions, creating a build-up of positive charge Z N N - general structure -=Z, where Z is more electronegative atom (e.g. -R, -N, -N 2 ) 9

10 - donation of electrons: - effect is greatest at the ortho and para positions, creating a build-up of negative charge X R N 2 - general structure -, where Z atom has a lone pair of electrons available for donation (e.g. -, -R, -N 2 ) Problem: What are the major products of the following reactions? a) mononitration of bromobenzene b) monobromination of aniline Explanation of Substituent Effects - must consider stability of the carbocation intermediate that forms upon ortho-, meta-, and para- substitution > > E E E E E E - activating groups donate electrons to the ring, thereby stabilizing the carbocation intermediate and causing it to form faster - deactiviting groups withdraw electrons from the ring, thereby destabilizing the carbocation intermediate and causing it to form more slowly 10

11 Nitration of Toluene Mechanism Nitration of Phenol Nitration of hlorobenzene 11

12 hlorination of Benzaldehyde Trisubstituted Benzenes - further electrophilic substitution of a disubstituted benzene is governed by the same resonance and inductive effects X X X ortho- meta- para- - must consider additive effects of the two groups on the ring Three rules to follow: 1) Directing effects can reinforce each other methyl group 3 3 N 3 N 2 2 S 4 N 2 N 2 nitro group p-nitrotoluene 2,4-dinitrotoluene 12

13 2) If the directing effects oppose each other, the more powerful activating group has the dominant influence Note: mixtures of products often result - 3) Substitution between two groups in a meta-disubstituted compound rarely occurs because the site is too hindered Fe 3 m-chlorotoluene 2,5-dichlorotoluene 2,3-dichlorotoluene 3,4-dichlorotoluene NT formed - must find alternative way to synthesize such compounds N 2 3 N 2 N S 4 N 2 2N 3 N 2 o-nitrotoluene 2,6-dinitrotoluene 2,4-dinitrotoluene Nucleophilic Aromatic Substitution (NAS) - aryl halides with an electron-withdrawing substitutent can undergo nucleophilic aromatic substitution 2N N N N N2 N2 2,4,6-trinitrobenzene 2,4,6-trinitrophenol (100%) 13

14 Mechanism of Reaction? - how does reaction occur? Neither S N 1 nor S N 2 - does not occur - instead, proceeds by addition/elimination mechanism Mechanism 14

15 Differences Between EAS and NAS Electrophilic Aromatic Substitution - favored by electron-donating substituents which stabilize the carbocation intermediate - electron-withdrawing groups deactivate - electron-withdrawing groups are meta directors Nucleophilic Aromatic Substitution - favored by electron-withdrawing subsitutents which stabilize the carbanion intermediate - electron-withdrawing groups activate - electron-withdrawing groups are ortho- and para- directors Benzyne - at high temperature and pressure, chlorobenzene can be forced to react to form phenol 1. Na, 2, 340 o, 2500 psi phenol synthesis takes place by way of an elimination/addition mechanism rather than addition/elimination - proceeds through a reactive benzyne intermediate Benzyne Intermediate elimination addition sp 2 hybridized sp 2 hybridized 15

16 Evidence for Benzyne Intermediate - radioactive 14 labeling experiments: * N2 bromobenzene * N - * 2 N 3 (-) benzyne (symmetrical) 50% N 3 * 50% N 2 aniline - reactivity experiments involving benzyne: KN 2 benzyne (dienophile) furan (diene) Diels-Alder product rbital Picture of Benzyne 16

17 xidation of Aromatic ompounds - benzene ring itself is inert to strong oxidizing agents (e.g. KMn 4, Na 2 r 2 7 ), which cleave alkene - bonds KMn 4 no reaction Na 2 r 2 7 no reaction xidation of Alkyl-Groups - alkyl-group side chains are readily attacked by oxidizing agents, being converted to carboxyl groups (-) 3 2 KMn 4 2, 95 o N 2 N 2 p-nitrotoluene p-nitrobenzoic acid (88%) KMn 4 2 butylbenzene benzoic acid - mechanism requires - bond at the position next to the aromatic ring to produce benzylic radicals Importance of Benzylic Radical 3 KMn no reaction 17

18 omination of Alkylbenzene Side hains - treatment of an alkylbenzene with N-bromosuccinimide results in side-chain bromination at the benzylic position N N (Ph 2 ) 2, 4 - mechanism is similar to allylic bromination of alkenes - involves a benzylic radical stabilized by resonance 18

19 Reduction of Aromatic ompounds - benzene rings are also inert to oxidation under most conditions - inert to catalytic hydrogenation under conditions that reduce typical alkenes - it is therefore possible to selectively reduce double bonds in the presence of an aromatic ring 2, Pd Ethanol 4-phenyl-3-buten-2-one 4-phenyl-3-butanone (100%) ydrogenation of Benzene - to hydrogenate benzene, harsh reaction conditions are necessary Examples - platinum catalyst under several hundred atmospheres of pressure 3 3 2, Pt; ethanol 2000 psi, 25 o rhodium catalyst on carbon 3 2, Rh/; ethanol 3 1 atm, 25 o Reduction of Aryl Alkyl Ketones - aromatic ring activates a neighboring carbonyl group toward reduction Example /Pd Al 3 propiophenone (95%) propylbenzene (100%) Al mixture of two products * avoids carbocation rearrangements * 19

20 - dialkyl ketones are not hydrogenated under these conditions 3 3 2, Pd/ Ethanol NT formed - -N 2 groups are reduced to an amino group under these conditions 2N 3 2, Pd/ Ethanol 2N 2 3 Synthesis of Trisubstituted Benzenes - a successful multistep synthesis of a complex molecule requires a working knowledge of many organic reactions - you need to know which reactions are available and when to use them - such a working knowledge may be developed in the synthesis of trisubstituted benzenes since the introduction of new substituents is strongly affected by directing effects of other substituents N 2 N 2 p-chloronitrobenzene m-chloropropylbenzene o-nitropropylbenzene N 3 2 S 4 N2 223 N 2 4-chloro-1-nitro-2-propylbenzene chloro-1-nitro-2-propylbenzene 20

21 2, Pd/ Ethanol 2 Fe Al 3 Total Synthesis Al 3 Fe 3 2, Pd/ Ethanol N 3 N 2 2 S 4 21