89
Reac%ons of Benzene and Subs%tuted Benzenes
Reac%ons of Benzene and Subs%tuted Benzenes
This Chapter Begins the Discussion of the Families of Compounds in Group IV
Many Subs%tuted Benzenes are Found in Nature
The Nomenclature of Subs%tuted Benzenes
some monosubs%tuted benzenes have names that incorporate the subs%tuent
• Benzene is aroma%c: a cyclic conjugated compound with 6 π electrons
• Reac%ons of benzene lead to the reten%on of the aroma%c core
Subs%tu%on Reac%ons of Benzene and Its Deriva%ves
The Way Benzene Reacts
Aroma%c compounds such as benzene undergo electrophilic aroma%c subs%tu%on reac%ons.
The π electrons above and below the ring make benzene a nucleophile.
Benzene Undergoes Subs%tu%on, Not Addi%on
Aroma%city is restored in the product from electrophilic subs%tu%on
Benzene Undergoes Subs%tu%on, Not Addi%on
The reac%on of benzene with an electrophile forms the aroma%c subs%tu%on product, not the nonaroma%c addi%on product.
The Mechanism for Electrophilic Aroma%c Subs%tu%on
• Bromina%on or chlorina%on of benzene requires a Lewis acid catalyst because benzene’s aroma%city causes it to be less reac%ve than an alkene.
• Ferric bromide (FeBr3) or ferric chloride (FeCl3) is usually used.
• FeBr3 is added as a catalyst to polarize the bromine reagent
• Benzene’s π electrons par%cipate as a Lewis base in reac%ons with Lewis acids
• The product is formed by loss of a proton, which is replaced by bromine
Electrophilic Aroma%c Subs%tu%on Reac%ons: Bromina%on or Chlorina%on
Addi%on Intermediate in Bromina%on
The intermediate is not aroma%c and therefore high in energy
• The ca%onic addi%on intermediate transfers a proton to FeBr4-‐ (from Br-‐ and FeBr3)
• This restores aroma%city (in contrast with addi%on in alkenes)
Forma%on of Product from Intermediate
• Chlorine and iodine (but not fluorine, which is too reac%ve) can produce aroma%c subs%tu%on with the addi%on of other reagents to promote the reac%on
• Chlorina%on requires FeCl3 • Iodine must be oxidized to form a more powerful I+ species
(with Cu+ or peroxide)
Other Aroma%c Subs%tu%ons
• The combina%on of nitric acid and sulfuric acid produces NO2+
(nitronium ion) • The reac%on with benzene produces nitrobenzene
Aroma%c Nitra%on
• Subs%tu%on of H by SO3H (sulfona%on) • Reac%on with sulfuric acid and heat, or a mixture of sulfuric
acid and SO3 • Reac%ve species is sulfur trioxide or its conjugate acid
Aroma%c Sulfona%on
Alkali Fusion of Aroma%c Sulfonates
Benzensulfonic Acid Phenol
SO3H
1) NaOH
2) H3O+
OH
Sulfona%on of Benzene is Reversible
The Mechanism for Desulfona%on:
If benzenesulfonic acid is heated in dilute acid, an H+ adds to the ring and the sulfonic acid group comes off the ring.
Aroma%c Hydroxyla%on
• Direct hydroxyla%on of an aroma%c ring difficult in the laboratory
• Usually occurs via an enzyme in biological pathways
Friedel–Craas Subs%tu%ons
• Two electrophilic subs%tu%ons are named for the chemists Charles Friedel and James Craas
• Friedel–Craas acyla%on places an acyl group on a benzene ring
• Friedel–Craas alkyla%on places an alkyl group on a benzene ring.
• Alkyla%on among most useful electrophilic aroma%c subsitu%on reac%ons
• Aroma%c subs%tu%on of R+ for H+
• Aluminum chloride promotes the forma%on of the carboca%on
Alkyla%on of Aroma%c Rings: The Friedel–Craas Reac%on
• Only alkyl halides can be used (F, Cl, I, Br) • Aryl halides and vinylic halides do not react (their carboca%ons
are too hard to form) • Will not work with rings containing an amino group subs%tuent
or a strongly electron-‐withdrawing group
Limita%ons of the Friedel-‐Craas Alkyla%on
• Mul%ple alkyla%ons can occur because the first alkyla%on is ac%va%ng
Control Problems
• Similar to those that occur during electrophilic addi%ons to alkenes
• Can involve H or alkyl shias
Carboca%on Rearrangements During Alkyla%on
• Reac%on of an acid chloride (RCOCl) and an aroma%c ring in the presence of AlCl3 introduces acyl group, ⎯COR – Benzene with acetyl chloride yields acetophenone
Acyla%on of Aroma%c Rings
Friedel–Craas Acyla%on
Mechanism:
• Similar to alkyla%on
• Reac%ve electrophile: resonance-‐stabilized acyl ca%on • An acyl ca%on does not rearrange
Mechanism of Friedel-‐Craas Acyla%on
The Gaderman–Koch Reac%on
• Benzaldehyde cannot be made by a Friedel–Craas acyla%on because the needed acyl chloride (formyl chloride) is unstable
• Formyl chloride is generated in the reac%on mixture
Electrophilic Aroma%c Subs%tu%on Reac%on
Pufng a Straight Chain Alkyl Group on a Ring
Other Ways to Convert a Carbonyl Group to a Methylene Group
Mechanism for the Wolff–Kishner Reduc%on
Coupling Reac%ons Can Be Used to Put a Straight Chain Alkyl Group on a
Benzene Ring
Why it is Important to Have More Than One Way to Carry Out a Reac%on
• Cataly%c hydrogena%on reduces aroma%c nitro groups and carbonyl groups.
• Wolff–Kishner reduc%on reduces only the carbonyl group.
Reduc%on of Benzene
OH
H
H
THE BIRCH REDUCTION: Aromatic rings are inert to catalyzed hydrogenation except under industriallyextreme conditions. A useful alternative to hydrogenation is the BIRCH REDUCTION. The resulting diene can then be readily hydrogenated to the corresponding alkene or alkane using H2/Pd.
H
HLi(0)NH3, EtOH
Li(0)
OH
Li(0)
• Aroma%c rings are inert to cataly%c hydrogena%on under condi%ons that reduce alkene double bonds
• Can selec%vely reduce an alkene double bond in the presence of an aroma%c ring
• Reduc%on of an aroma%c ring requires more powerful reducing condi%ons (high pressure or rhodium catalysts)
Reduc%on of Aroma%c Compounds
• Aroma%c ring ac%vates neighboring carbonyl group toward reduc%on
• Ketone is converted into an alkylbenzene by cataly%c hydrogena%on over Pd catalyst
Reduc%on of Aryl Alkyl Ketones
Subs%tuents on a Benzene Ring Can Be Chemically Changed
• Bromine will selec%vely subs%tute for a benzylic hydrogen in a radical subs%tu%on reac%on.
• A halogen at the benzylic posi%on can lead to subs%tu%on or elimina%on.
• Reac%on of an alkylbenzene with N-‐bromo-‐succinimide (NBS) and benzoyl peroxide (radical ini%ator) introduces Br into the side chain
Bromina%on of Alkylbenzene Side Chains
• Abstrac%on of a benzylic hydrogen atom generates an intermediate benzylic radical
• Reacts with Br2 to yield product • Br· radical cycles back into reac%on to carry chain • Br2 produced from reac%on of HBr with NBS
Mechanism of NBS (Radical) Reac%on
The Benzene Ring is Reduced Only at High Temperature and Pressure
Alkyl Subs%tuents are Oxidized to Carboxyl Groups
• Alkyl side chains can be oxidized to ⎯CO2H by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C–H next to the ring
• Converts an alkylbenzene into a benzoic acid, Ar⎯R → Ar⎯CO2H
Oxida%on of Aroma%c Compounds
Nitro Subs%tuents are Reduced by Cataly%c Hydrogena%on
The Effect of Subs%tuents on Reac%vity
• Subs%tuents that donate electron density to the benzene ring increase benzene’s nucleophilicity and stabilize the carboca%on intermediate.
• Subs%tuents that withdraw electron density to the benzene ring decrease benzene’s nucleophilicity and destabilize the carboca%on intermediate.
• Subs%tuents can cause a compound to be (much) more or (much) less reac%ve than benzene
• Subs%tuents affect the orienta%on of the reac%on – the posi%onal rela%onship is controlled – ortho-‐ and para-‐direc%ng ac%vators, ortho-‐ and para-‐direc%ng
deac%vators, and meta-‐direc%ng deac%vators (Table 16.1)
Subs%tuent Effects in Subs%tuted Aroma%c Rings
• An interplay of induc4ve effects and resonance effects • Induc%ve effect -‐ withdrawal or dona%on of electrons through a σ bond
• Resonance effect -‐ withdrawal or dona%on of electrons through a π bond due to the overlap of a p orbital on the subs%tuent with a p orbital on the aroma%c ring
Origins of Subs%tuent Effects
• Controlled by electronega%vity and the polarity of bonds in func%onal groups
• Halogens, C=O, CN, and NO2 withdraw electrons through σ bond connected to ring
• Alkyl groups donate electrons
Induc%ve Effects
• C=O, CN, NO2 subs%tuents withdraw electrons from the aroma%c ring by resonance
• π electrons flow from the rings to the subs%tuents
Resonance Effects – Electron Withdrawal
• Halogen, OH, alkoxyl (OR), and amino subs%tuents donate electrons
• π electrons flow from the subs%tuents to the ring • Effect is greatest at ortho and para
Resonance Effects – Electron Dona%on
Strongly Ac%va%ng Subs%tuents
• All the strongly ac%va%ng subs%tuents donate electrons by resonance.
• All the strongly ac%va%ng subs%tuents withdraw electrons induc%vely.
• Because the subs%tuents are ac%va%ng, electron dona%on by resonance is more significant than induc%ve electron withdrawal.
Moderately Ac%va%ng Subs%tuents
Moderately ac%va%ng subs%tuents donate electrons by resonance.
• Ac%va%ng groups donate electrons to the ring, stabilizing the Wheland intermediate (carboca%on)
• Deac%va%ng groups withdraw electrons from the ring, destabilizing the Wheland intermediate
An Explana%on of Subs%tuent Effects
• Alkyl groups ac%vate: direct further subs%tu%on to posi%ons ortho and para to themselves
• Alkyl group is most effec%ve in the ortho and para posi%ons
Ortho-‐ and Para-‐Direc%ng Ac%vators: Alkyl Groups
• Alkoxyl, and amino groups have a strong, electron-‐dona%ng resonance effect
• Most pronounced at the ortho and para posi%ons
Ortho-‐ and Para-‐Direc%ng Ac%vators: OH and NH2
• Electron-‐withdrawing induc%ve effect outweighs weaker electron-‐dona%ng resonance effect
• Resonance effect is only at the ortho and para posi%ons, stabilizing carboca%on intermediate
Ortho-‐ and Para-‐Direc%ng Deac%vators: Halogens
• Induc%ve and resonance effects reinforce each other • Ortho and para intermediates destabilized by deac%va%on of
carboca%on intermediate • Resonance cannot produce stabiliza%on
Meta-‐Direc%ng Deac%vators
Summary Table: Effect of Subs%tuents in Aroma%c Subs%tu%on
Subs%tuents on the Benzene Ring Affect the pKa
electron dona%ng groups decrease the acidity (destabilize the conjugate base) electron withdrawing groups increase the acidity (stabilize the conjugate base)
Subs%tuents on the Benzene Ring Affect the pKa
Reac%ons of Monosubs%tuted Benzene
Halogena%on with a Strongly Ac%va%ng Group Present
Friedel–Craas Reac%ons Do Not Occur with Meta Directors
Aniline Must Be Protected in Order to Be Nitrated
• Aniline cannot be nitrated directly because nitric acid will oxidize an NH2 group.
• If the amino group is protected by acetyla%on, the ring can be nitrated.
• An acetyl group is removed by acid-‐catalyzed hydrolysis.
Synthesis
OH
The Order of the Reac%ons is Important
• If the direc%ng effects of the two groups are the same, the result is addi%ve
Trisubs%tuted Benzenes: Addi%vity of Effects
• If the direc%ng effects of two groups oppose each other, the more powerful ac%va%ng group decides the principal outcome
• Usually gives mixtures of products
Subs%tuents with Opposite Effects
• The reac%on site is too hindered • To make aroma%c rings with three adjacent subs%tuents, it is best to start
with an ortho-‐disubs%tuted compound
Meta-‐Disubs%tuted Compounds
Nucleophilic Aroma%c Subs%tu%on
Aryl halides do not react with nucleophiles because a nucleophile is repelled by the π electron cloud.
Two different pathways are available for nucleophilic aroma%c subs%tu%on:
1) Bimolecular displacement mechanism for ac%vated aryl halides 2) Elimina%on-‐addi%on mechanism (Benzyne intermediate forma%on)
Nucleophilic Aroma%c Subs%tu%on
Bimolecular Displacement Mechanism X
G
G#=#SO3H,#COOH,#COR,#NR3+,#NO2,#NO,#CN#located#ortho#or#para#to#halogen#(leaving#group)
Nu
Nu
G
+##X
In#nucleophilic#aromatic#substitution#reactions,####!electron!withdrawing!group#causes#activation#(stabalizes#carbanion)#####electron!donating!group#causes#deactivation#(destabalizes#carbanion)####OPPOSITE#TO#ELECTROPHILIC#AROMATIC#SUBSTITUTION
Nucleophilic Aroma%c Subs%tu%on
Bimolecular Displacement Mechanism
The Mechanism for Nucleophilic Aroma%c Subs%tu%on
• The nucleophile adacks the carbon bonded to the leaving group from a trajectory that is nearly perpendicular to the aroma%c ring.
• The leaving group is eliminated, reestablishing the aroma%city of the ring.
Why the Electron Withdrawing Groups Must Be Ortho or Para to the Site of
Adack
• Electrons can be delocalized onto ortho and para subs%tuents.
• Electrons cannot be delocalized onto a meta subs%tuent.
• Aryl halides with electron-‐withdrawing subs%tuents ortho and para react with nucleophiles
• Form addi%on intermediate (Meisenheimer complex) that is stabilized by electron-‐withdrawal
• Halide ion is lost to give aroma%c ring
Nucleophilic Aroma%c Subs%tu%on
Many Nucleophiles Can Engage in Nucleophilic Aroma%c Subs%tu%on
• The nucleophile must be a stronger base than the leaving group.
Nucleophilic Aroma%c Subs%tu%on
• Elimina%on-‐addi%on method
• Needs a strong base, and must have Hydrogen ortho to a leaving group (halogen)
• Forms benzyne intermediate
• Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure
• The reac%on involves an elimina%on reac%on that gives a triple bond
• The intermediate is called benzyne
Benzyne
• Benzyne is a highly distorted alkyne • The triple bond uses sp2-‐hybridized carbons, not the usual sp • The triple bond has one π bond formed by p–p overlap and
another by weak sp2–sp2 overlap
Structure of Benzyne
• Bromobenzene with 14C only at C1 gives subs%tu%on product with label scrambled between C1 and C2
• Reac%on proceeds through a symmetrical intermediate in which C1 and C2 are equivalent— must be benzyne
Evidence for Benzyne as an Intermediate
Synthesis of an Arenediazonium Salt
The synthesis and denitrifica%on of diazonium salts is one of the most effec%ve methods for introducing a nucleophile to a benzene ring. The condi%ons are milder than those for nucleophilic aroma%c subs%tu%on and yields are generally good.
NH2HNO2,&H2SO4
0&°C
NN
+""HSO4""""+""2"H2ONu
Nu
+&&N2
Mechanism for Forma%on of the Nitrosonium Ion
• Hydrochloric acid protonates the nitrite ion, forming nitrous acid.
• Hydrochloric acid protonates nitrous acid. • Protonated nitrous acid loses water to form the nitrosonium ion.
• The nitrosonium ion is the electrophile required to form a diazonium ion.
Sandmeyer Reac%ons
Mechanism for Diazonium Ion Forma%on
The Sandmeyer Reac%on Can Be a Useful Alterna%ve for Halogena%on
• Chlorina%on of ethylbenzene leads to a mixture of ortho and para isomers
• A Sandmeyer reac%on forms only the para product.
Aryl Fluorides and Iodides Can Be Made
from Arenediazonium Salts
Phenols Can Be Made from Arenediazonium Salts
• An acidic aqueous solu%on of a diazonium salt that warms up forms a phenol.
• Copper(I) oxide and copper(II) nitrate can be added to get a higher yield of a phenol.
A Diazonium Group Can Be Replaced by a Hydrogen
The Arenediazonium Ion Reacts as an Electrophile with Highly Ac%vated
Rings
• The product of the reac%on is an azo compound. • The N═N linkage is called an azo linkage.
The Mechanism
• The electrophile adds to the benzene ring. • A base in the solu%on removes the proton from the carbon that formed the bond with the electrophile.
Azo Compounds Have Geometric Isomers
