University:
Kentucky State University
Course:
CHE 302 | Organic Chemistry II
Academic year:

2024
Views:

64

Pages:

38
Author:

Lily Callahan

16. Chemistry of Benzene: Electrophilic Aromatic Substitution Substitution Reactions of Benzene and Its Derivatives ◼ Benzene is aromatic: a cyclic conjugated compound with 6  electrons ◼ Reactions of benzene lead to the retention of the aromatic core Why this Chapter? ◼ Continuation of coverage of aromatic compounds in preceding chapter…focus shift to understanding reactions ◼ Examine relationship between aromatic structure and reactivity ◼ Relationship critical to understanding of how biological molecules/pharmaceutical agents are synthesized Electrophilic Aromatic Bromination ◼ Benzene’s  electrons participate as a Lewis base in ◼ ◼ ◼ ◼ ◼ reactions with Lewis acids The product is formed by loss of a proton, which is replaced by bromine FeBr3 is added as a to polarize the bromine reagent In the first step the  electrons act as a nucleophile toward Br2 (in a complex with FeBr3) This forms a cationic addition intermediate from benzene and a bromine cation The intermediate is not aromatic and therefore high in energy Formation of Product from Intermediate ◼ The cationic addition intermediate transfers a proton to FeBr4- (from Brand FeBr3) ◼ This restores aromaticity (in contrast with addition in alkenes) Other Aromatic Halogenations ◼ Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution with the addition of other reagents to promote the reaction ◼ Chlorination requires FeCl3 ◼ Iodine must be oxidized to form a more powerful I+ species (with Cu2+ from CuCl2) Aromatic Nitration ◼ The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion) ◼ The reaction with benzene produces nitrobenzene ◼ The Nitro group can be reduced to an Amino group if needed Aromatic Sulfonation ◼ Substitution of H by SO3 (sulfonation) ◼ Reaction with a mixture of sulfuric acid and SO3 (“Fuming H2SO4) ◼ Reactive species is sulfur trioxide or its conjugate acid ◼ Sulfonamides are “sulfa drug” antibiotics Alkylation of Aromatic Rings: The Friedel–Crafts Reaction ◼ Alkylation among most useful electrophilic aromatic substitution reactions ◼ Aromatic substitution of R+ for H+ ◼ Aluminum chloride promotes the formation of the carbocation Limitations of the Friedel-Crafts Alkylation ◼ Only alkyl halides can be used (F, Cl, I, Br) ◼ Aryl halides and vinylic halides do not react (their carbocations are too hard to form) ◼ Will not work with rings containing an amino group substituent or a strongly electron-withdrawing group Other Problems with Alkylation ◼ Multiple alkylations can occur because the first alkylation is activating ◼ Carbocation Rearrangements Occur During Alkylation ◼ Similar to those occuring during electrophilic additions to alkene ◼ Can involve H or alkyl shifts Acylation of Aromatic Rings ◼ Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, ⎯COR ◼ Benzene with acetyl chloride yields acetophenone ◼ ◼ Avoids many of the problems of alkylation ◼ Only substitutes once, because acyl group is deactivating ◼ No rearrangement because of resonance stabilized cation Mechanism of Friedel-Crafts Acylation ◼ Similar to alkylation ◼ Reactive electrophile: resonance-stabilized acyl cation ◼ An acyl cation does not rearrange ◼ Can reduce carbonyl to get alkyl product Substituent Effects in Aromatic Rings ◼ Substituents can cause a compound to be (much) more or (much) less reactive than benzene ◼ Substituents affect the orientation of the reaction – the positional relationship is controlled ◼ ortho- and para-directing activators, ortho- and para- directing deactivators, and meta-directing deactivators. Origins of Substituent Effects ◼ An interplay of inductive effects and resonance effects ◼ Inductive effect - withdrawal or donation of electrons through a s bond = Polar Covalent Bonds ◼ Resonance effect - withdrawal or donation of electrons through a  bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring Inductive Effects ◼ Controlled by electronegativity and the polarity of bonds in functional groups ◼ Halogens, C=O, CN, and NO2 withdraw electrons through s bond connected to ring ◼ Alkyl groups donate electrons Resonance Effects – Electron Withdrawal ◼ C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance ◼  electrons flow from the rings to the substituents ◼ Look for a double (or triple) bond connected to the ring by a single bond Resonance Effects – Electron Donation ◼ Halogen, OH, alkoxyl (OR), and amino substituents donate electrons ◼  electrons flow from the substituents to the ring ◼ Effect is greatest at ortho and para positions ◼ Look for a lone pair on an atom attached to the ring An Explanation of Substituent Effects ◼ Activating groups donate electrons to the ring, stabilizing the carbocation intermediate ◼ Deactivating groups withdraw electrons from the ring, destabilizing carbocation intermediate Ortho/Para-Directing Activators: Alkyl Groups ◼ Alkyl groups activate by induction: direct further substitution to positions ortho and para to themselves ◼ Alkyl group has most effect on the ortho and para positions Ortho/Para-Directing Activators: OH and NH2 ◼ Alkoxyl, and amino groups have a strong, electron- donating resonance effect ◼ Most pronounced at the ortho and para positions Ortho/Para-Directing Deactivators: Halogens ◼ Electron-withdrawing inductive effect outweighs weaker electron- donating resonance effect ◼ Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate Meta-Directing Deactivators ◼ Inductive and resonance effects reinforce each other ◼ Ortho and para intermediates destabilized by deactivation of carbocation intermediate ◼ Resonance cannot produce stabilization Summary Table: Effect of Substituents in Aromatic Substitution Trisubstituted Benzenes: Additivity of Effects ◼ If the directing effects of the two groups are the same, the result is additive ◼ If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome ◼ Usually gives mixtures of products Meta-Disubstituted Compounds ◼ The reaction site is too hindered ◼ To make aromatic rings with three adjacent substituents, it is best to start with an orthodisubstituted compound Nucleophilic Aromatic Substitution ◼ Aryl halides with electron-withdrawing substituents ortho and para react with nucleophiles (electron withdrawing needed to accept electrons from the nucleophile) ◼ Form addition intermediate (Meisenheimer complex) that is stabilized by electron-withdrawal. Halide is leaving group. 27 Nucleophilic Aromatic Substitution Benzyne: Substitution of Unactivated Aromatics ◼ Phenol is prepared industrially by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure ◼ The reaction involves an elimination reaction that gives a triple bond in the ring: benzyne Structure of Benzyne ◼ Benzyne is a highly distorted alkyne ◼ The triple bond uses sp2-hybridized carbons, not the usual sp ◼ The triple bond has one  bond formed by p–p overlap and another by weak sp2–sp2 overlap Oxidation of Aromatic Compounds ◼ Alkyl side chains can be oxidized to ⎯CO2H by strong reagents such as KMnO4 if they have a C-H next to the ring ◼ Converts an alkylbenzene into a benzoic acid, Ar⎯R → Ar⎯CO2H ◼ A benzylic C-H bond is required, or no reaction takes place Bromination of Alkylbenzene Side Chains ◼ Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain only at benzylic position Reduction of Aromatic Compounds ◼ Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds ◼ Can selectively reduce an alkene double bond in the presence of an aromatic ring ◼ Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium s) Reduction of Aryl Alkyl Ketones ◼ Aromatic ring activates neighboring carbonyl group toward reduction ◼ Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd Synthesis of Trisubstituted Benzenes ◼ These syntheses require planning and consideration of alternative routes ◼ Ability to plan a sequence of reactions in right order is valuable to synthesis of substituted aromatic rings

16. Chemistry of Benzene Electrophilic Aromatic Substitution

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