Lecture 11 and 12 The Page Lectures
• Electrophylic Aromatic Substitution
H H H H H H + E+ H E + H+ H H H H
February 26 and 28 2019 Chemistry 328N
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l front Br ??
l Back
NBS ??? CCl4
Chemistry 328N
1 Electrophilic Aromatic Substitution
§ Electrophilic aromatic substitution: a reaction in which a hydrogen atom on an aromatic ring is replaced by an electrophile
§ We study § several common types of electrophiles, § how they are generated, and § the mechanism by which they replace hydrogen, which is the same for all
Chemistry 328N
Substiution vs Addition
Chemistry 328N
2 Electrophilic Aromatic Substitution
H + + E H + H+ E E
Please be sure All EAS reactions H that you can do + follow this path so we H this and that it only need to learn E makes sense to how to make different you!! electrophiles, E+
H + E H Chemistry 328N
The Energetics
H H E H + H H H
H H H H H H + E+ H E + H+ H H H H Chemistry 328N
3 Nitration
NO2 H2SO4
HNO3
H •• + H O NO2 + H O SO 3H H O NO2 + HSO 4 •• •• Nitric acid H H •• •• •• + •••• H +O NO H O + O=N=O •• 2 •• Nitronium ion Chemistry 328N
Chlorination
l Chlorination requires requires a Lewis acid catalyst, such as AlCl3 or FeCl3
Cl
•• •• •••• Cl Cl + Fe Cl •• •• chloronium Cl ion Cl + + - •• •• •• •• - •• Cl Cl Fe Cl Cl FeCl 4 •• •• •• Cl Chemistry 328N
4 Sulfonation
H2 SO 4 H + SO 3 SO 3 H Benzenesulfonic acid
+ H O H S O O O S - O O
Sulfonation can be reversed by Heating in H2O
Chemistry 328N
The Friedel-Crafts Reaction.. Circa 1877
Charles Friedel James Craft
Making C-C bonds is….
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5 Friedel-Crafts Alkylation
CH2 CH3CH2Cl CH3
AlCl3
Cl
•••• R Cl + Al Cl •• Cl Cl ••+ - + - R Cl Al Cl R AlCl •• 4 An ion pair Cl containing a carbocation Chemistry 328N
A word about the Friedel-Crafts Alkylation
1. Carbocation rearrangements are common
CH3 AlCl 3 + CH CHCH Cl 3 2 C(CH 3 )3 + HCl Benzene Isobutyl chloride tert-Butylbenzene
Chemistry 328N
6 Friedel-Crafts Alkylation
2. They are tough to stop!
Product is more reactive than the starting material Hence. Terrible mixtures result….
CH CH Cl 3 2 + + etc. AlCl3
Chemistry 328N
Role of AlCl3 Acts as a Lewis acid to promote ionization of the alkyl halide
+ •• – • •• (CH3)3C Cl + AlCl3 (CH3)3C Cl AlCl3 •• • ••
+ – • (CH3)3C + •Cl AlCl3 •• Chemistry 328N
7 Friedel-Crafts Alkylation
alkylation fails on benzene rings bearing one or more strongly electron-withdrawing groups
O O O O O
CH CR COH COR CNH 2 + SO 3H C N NO2 NR 3
CF 3 CCl 3
Chemistry 328N
Friedel-Crafts Acylation
O O AlX H + RCX 3 CR + HX An acylbenzene
O Cl O Cl O + - •• •• + - • • R-C Cl Al Cl R-C AlCl R-C Cl + Al-Cl •• 4 •• An ion pair Cl containing Cl an acylium ion
Chemistry 328N
8 Friedel-Crafts Acylation l An acylium ion is a resonance hybrid of two major contributing structures
+ + R C O R C O
– F-C acylations are free of TWO major limitation of F-C alkylations; acylium ions do not rearrange and the product is deactivating so the reaction stops after one substitution!!!
Chemistry 328N
H E d+ d– + E Y + H Y
Electrophilic aromatic substitutions include:
Nitration Sulfonation Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation
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9 Hydrogenolysis
O
H2 CH3COCl
AlCl3 Pd/C
There are two nice tricks hidden here Works on benzylic alcohol and ethers as well. Please be sure to remember this reaction!!!
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How to make ethyl benzene
Chemistry 328N
10 Di- and Polysubstitution l Existing groups on a benzene ring influence further substitution in both orientation and rate l Orientation: – certain substituents direct preferentially to ortho & para positions; others direct preferentially to meta positions – substituents are classified as either ortho-para directing….. or meta directing
Chemistry 328N
Di- and Polysubstitution l Rate: – certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower – substituents are classified as
• activating toward further substitution, or
• deactivating
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11 Di- and Polysubstitution
l -OCH3 is ortho-para directing and activating
OCH OCH 3 OCH 3 3 Br Br 2 + + HBr CH 3 CO 2 H Anisole Br o-Bromo- p-Bromo- anisole anisole (4%) (96%)
Chemistry 328N
Di- and Polysubstitution
l -NO2 is meta directing and deactivating!
NO 2 H 2 SO 4 + HNO 3 NO 2 NO 2 NO 2 Nitro- NO 2 benzene + + NO 2 NO 2 m-Dinitro- o-Dinitro- p-Dinitro- benzene benzene benzene (93%) Less than 7% combined
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12 Methyl Group
CH3 Toluene undergoes nitration 1000 times faster than benzene. A methyl group is an activating substituent.
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Trifluoromethyl Group
CF3 Trifluoromethylbenzene undergoes nitration 40,000 times more slowly than benzene . The trifluoromethyl group is a deactivating substituent.
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13 Relative rates of Nitration
OH H Cl NO2
1000 1.0 0.033 6x10-8
Reactivity
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Real Fast
Pretty fast
Kinda slow
Pretty slow
Slow
Real Slow
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14 Di- and Polysubstitution
Some observations l Alkyl groups, phenyl groups, and all groups in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other groups are meta directing. l All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating
Chemistry 328N
Effect on Regioselectivity
• Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. • Meta directors direct an incoming electrophile to positions meta to themselves.
• All meta directors are deactivating
• All ortho-para directors are activating except halogen
Chemistry 328N
15 Theory of Directing Effects
• So…what’s going on here????
• The rate of EAS is limited by the slowest step in the mechanism…duh
• For EAS, the rate-limiting step is attack of E+ on the aromatic ring to form a resonance-stabilized cation intermediate
• The more stable this cation intermediate, the faster the rate-limiting step and the faster the overall reaction
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Adding a Second Substiuent
Methoxy is is therefore an “o-p director” Chemistry 328N
16 Adding a Second Substiuent
Meta attack is not good, but better than the alterntive! Nitro is therefore a “meta director” Chemistry 328N
Di- and Polysubstitution
CH 3 CO2H
HNO3 K 2 Cr 2 O7
H2SO 4 H2 SO 4 CH 3 NO2 NO2 p-Nitrobenzoic acid
CO2H CO2H HNO K 2 Cr 2 O7 3 H SO H2SO 4 2 4 NO2 m-Nitrobenzoic acid
Chemistry 328N
17 ortho Nitration of Toluene
CH3 NO2 H H + H H
H
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ortho Nitration of Toluene
CH3 CH3 NO2 NO2 H H H H + + H H H H
H H
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18 ortho Nitration of Toluene
CH3 CH3 CH3 NO2 NO2 NO2 H H H + H H H + + H H H H H H
H H H this resonance form is a tertiary carbocation
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ortho Nitration of Toluene
CH3 CH3 CH3 NO2 NO2 NO2 H H H + H H H + + H H H H H H
H H H
the rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation character Chemistry 328N
19 meta Nitration of Toluene
CH3 H H +
H H
NO2 H
Chemistry 328N
meta Nitration of Toluene
CH3 CH3 H H H H + +
H H H H
NO2 NO2 H H
Chemistry 328N
20 meta Nitration of Toluene
CH3 CH3 CH3 H H H H H H + +
H H H H H + H
NO2 NO2 NO2 H H H all the resonance forms of the rate-determining intermediate in the meta nitration of toluene have their positive charge on a secondary carbon
Chemistry 328N
Nitration of Toluene: Interpretation
l The rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations.
l Tertiary carbocations, being more stable, are formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. This explains why the major products are o- and p-nitrotoluene.
Chemistry 328N
21 Nitration of Toluene: Partial Rate Factors
l The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions.
l Expressed as a numerical value, a partial rate factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene.
Chemistry 328N
Nitration of Toluene: Partial Rate Factors
CH3 1 1 1 42 42 1 1 2.5 2.5 1 58
l All ring positions in toluene are more reactive than any position of benzene. l A methyl group activates all of the ring positions but the effect is greatest at the ortho and para positons. l Steric hindrance by the methyl group makes each ortho position slightly less reactive than para. Chemistry 328N
22 Synthesis of m-Bromoacetophenone
Br
CH3
O CH3
Br O Which substituent should be introduced first?
Chemistry 328N
Factors to Consider
The order of the introduction of substituents must be carefully designed to ensure correct orientation
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23 Synthesis of m-Bromoacetophenone
Br Which substituent should be introduced first?
O
CCH3
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Synthesis of m-Bromoacetophenone
Br para
If bromine is introduced first, p-bromoacetophenone is major product. O
CCH3 meta
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24 Synthesis of m-Bromoacetophenone
Br O
CCH3
O Br2
CH3C-Cl AlCl O 3
AlCl3 CCH3
Chemistry 328N
Starting with Benzene, make this...
Work Backwards!! Br
CH3CH2Cl AlCl Br 3 Br O H2, Pd/C Br2 FeBr3
Br Br2 O O FeBr3 CH3C Cl
AlCl3
Chemistry 328N
25 Di- and Polysubstitution
CH3 CO2H HNO 3 K2Cr 2O7
H2SO4 H2SO 4 CH 3 NO2 NO 2 p-Nitrobenzoic acid
CO2H CO2H K 2Cr 2O7 HNO3
H 2SO 4 H2SO4 NO2 m-Nitrobenzoic acid
Chemistry 328N
Multiple Substituent Effects
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26 The Simplest Case
all possible EAS sites may be equivalent
CH3 CH3 O O CCH AlCl3 3
+ CH3C-Cl
CH3 CH3 99%
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Another Straightforward Case
CH3 CH3 Br Br2 Fe
NO2 NO2 86-90% directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group Chemistry 328N
27 Generalization
regioselectivity is controlled by the most activating substituent
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The “Best Man Wins”
strongly NHCH3 NHCH3 activating Br Br2
FeBr3
Cl Cl 87%
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28 When activating effects are similar...
CH3 CH3
HNO3 NO2
H2SO4
C(CH3)3 C(CH3)3 88%
substitution occurs ortho to the smaller group
Chemistry 328N
Steric effects control regioselectivity when electronic effects are similar
CH3 CH3
HNO3
H2SO4 CH3 CH3
NO2 98% position between two substituents is last position to be substituted Chemistry 328N
29 Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics
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Substitution in Heterocyclic Aromatic Compounds
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30 Generalization
There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible.
Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive..
Chemistry 328N
Pyridine
N l Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. l Presence of electronegative atom (N) in ring causes p electrons to be held more strongly than in benzene.
Chemistry 328N
31 Pyridine
SO3, H2SO4 SO3H
HgSO4, 230°C N N
71%
Pyridine can be sulfonated at high temperature.
EAS takes place at C-3.
Chemistry 328N
Pyrrole, Furan, and Thiophene
•• •• •• N O S •• •• H Have 1 less ring atom than benzene or pyridine to hold same number of p electrons (6). p electrons are held less strongly…rings are more “electron rich”. These compounds are quite reactive toward EAS.. Chemistry 328N
32 Example: Furan
O O AlCl3 + CH3CCl O CCH O 3 75-92%
undergoes EAS readily C-2 is most reactive position
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Reduction of the Nitro Group
Aniline !
The Nitro group is easily reduced. Many reducing agents can be employed for this transformation including Sn or Fe in HCl, H2 with Pd/C, etc
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33 Aniline dyes (Tyrian Purple)
Royal Purple Previously from shell fish secretions
Aniline Dye Chemistry 328N
Diazonium Salts
Diazonium Salt
Acts like Chemistry 328N
34 Mechanism of Diazonium Salt formation
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Reactions of Diazonium Salts
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35 Diazonium Salts
+ l The -N2 group of an arenediazonium salt can be replaced in a regioselective manner by these groups H O 2 Ar-OH HBF 4 Ar-F Schiemann reaction HCl, CuCl Ar-Cl + Sandmeyer Ar-N (-N 2) HBr, CuBr 2 Ar-Br reaction KCN, CuCN Ar-CN KI Ar-I H PO 3 2 Ar-H Chemistry 328N
Practice
CH 3 Cl
CH 3 CH 3 CH 3 NH2 C N CH 2NH2
CH 3 CH 3 NH2
Cl Cl Cl Cl
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36 Practice…work backwards Oh No….two o,p directors meta to one another???
?????
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Synthesis Strategy
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37 Substitution Reactions l Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 pathways!
But…..
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But….this is fact l When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide
Cl O-Na + H O + 2NaOH 2 + NaCl + H O pressure, 300oC 2 Chloro- Sodium benzene phenoxide
– neutralization with HCl gives phenol????? What is this??
Chemistry 328N
38 Also fact…. l The same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol???? Ortho and meta….huh????
CH3 CH3 CH3 Cl OH 1. NaOH, heat, pressure + 2. HCl, 2 OH OH 2-Methylphenol3- Methylphenol (o-Cresol) (m-Cresol)
Chemistry 328N
Also true l The same type of reaction can be brought about by the use of sodium amide in liquid ammonia
CH 3 CH 3 CH 3
NH 3 (l) + NaNH + NaCl 2 (-33 oC) + NH Cl 2 NH 2
Chemistry 328N
39 Proposed Benzyne Intermediate
l b-elimination of HX gives a “benzyne” intermediate, that then adds the nucleophile to give products
CH 3 CH 3
NaNH 2 b-elimin- H Cl ation A benzyne intermediate
Chemistry 328N
Proposed Benzyne Intermediate
Chemistry 328N
40 Proposed Benzyne Intermediate
Another Mystery??
CF3 CF3
Cl NH3(l)
NaNH2 NH2
More than 95% of the product is the meta isomer??
Chemistry 328N
Nucleophilic Addition-Elimination
l When an aryl halide contains strongly electron- withdrawing -NO2 groups ortho and/or para to X, nucleophilic aromatic sub. takes place readily
Cl O- Na + NO NO 2 Na 2 CO 3, H 2O 2 100 oC
NO2 NO2 1-Chloro-2,4-dinitrobenzene Sodium 2,4-dinitrophenoxide
Chemistry 328N
41 Meisenheimer Complex
•• •• O slow, rate-
•• - limiting +N Cl + Nu
•• •• (1) O - •• NO2
•• ••••
- •• •• O O Cl fast - +N +N Nu + Cl
•• •• (2) •• Nu •• O •• O - NO2 - •• NO2 A Meisenheimer complex
Chemistry 328N
Addition Elimination
F OCH3 - CH3O
CH3OH
NO2 NO2
Chemistry 328N
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