Aromaticity & Aromatic Substitution Reactions · PDF fileBenzene and Aromaticity...

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Aromaticity andAromaticity andAromaticity and Aromaticity and Aromatic Substitution ReactionsAromatic Substitution Reactions

McMurryMcMurry: Chapter: Chapter 15 and 1615 and 16McMurryMcMurry: Chapter : Chapter 15 and 1615 and 16

My contact info:

Prof. Mitch Winnik

m.winnik@utoronto.ca

Office hours: Thursdays 2 4 PMOffice hours: Thursdays 2–4 PM

Office: LM520 (fifth floor, Lash Miller building, 80 St. George St.)

Benzene and Aromaticity

Historically: fragrant substances isolated from natureHistorically: fragrant substances isolated from nature

Chemically: these compounds contain a benzene ring (conjugated

t t ith i 2 h b idi d b )structure with six sp2‐hybridized carbons)

H3C CH3Benzaldehyde (almonds) Thymol (thyme)

Cinnamaldehyde (cinnamon)39e p 451

Nomenclature: Common Names

Most aromatic compounds are named according to IUPACMost aromatic compounds are named according to IUPAC rules, but some have common names:

CHNH CH3NH2

Phenol TolueneAniline

Acetophenone Benzaldehyde Benzoic AcidStyrene

49e pp 452–455

Terminology: Benzene Substitution Patterns

ortho meta para

59e pp 452–455

Nomenclature

Number the groups to give the lowest possible number and thenNumber the groups to give the lowest possible number and then name them in alphabetical order. Parent name can be ‐benzeneor a common name:

69e pp 452–455

Nomenclature: Alkyl Substitution

If the alkyl group is ≤ 6 C, it’s a substituted benzene:y g p ,

If the alkyl group is > 6 C, it’s a substituted alkane:

79e pp 452–455

IR and NMR of Aromatic CompoundsIR: C‐H (sp2): 3090–3000 cm–1, C=C: 1625–1450 cm‐1, Ring bends:900–670 cm–1:

Aromatic 1H: δ 6.5–8.0 ppm Aromatic 13C: δ 110–175 ppm

13C NMR1H NMR

89e pp 469–474

Benzene

• Each bond length is 1.39 Å (C–C: 1.54 Å and C=C: 1.34 Å)• Planar cyclic and conjugated• Planar, cyclic and conjugated• Bond angles of 120°• All carbons are sp2 hybridized and have a p‐orbital

l d d l l d ll b d• Electron density is delocalized among all π bonds

99e pp 456–458

What Makes Something Aromatic?

Hückel’s RulesHückel s Rules Aromatic:

• 4n + 2 electrons, where n is an integer , g• Cyclic• Planar• Conjugated• Conjugated

Anti‐Aromatic:

• 4n electrons, where n is an integer • Cyclic• Planar

E i h Hü k l• Conjugated

Doesn’t fit either? It’s Non‐Aromatic

Erich Hückel (1931)

109e pp 459–461

Why Are Aromatic Compounds So Stable?

Aromatic: 4n + 2 π electrons (2 6 10 ) fill the molecularAromatic: 4n + 2 π electrons (2, 6, 10…) fill the molecular orbitals at each energy level, leading to increased stabilization

A i A i 4 l (4 8 12 ) l i ll fillAnti‐Aromatic: 4n π electrons (4, 8, 12…) only partially fill the molecular orbitals at a particular energy level leading to decreased stabilization

anti‐bonding orbitals

bonding orbitals

119e pp 459–461

Aromatic, Anti‐Aromatic or Non‐Aromatic?

Benzene

Electrons: 6A ti 4 2 ( ?) 1Aromatic 4n+2 (n=?) n = 1Anti‐aromatic 4n (n=?)

Cyclic: YESCyclic: YES

Conjugated: YES

Planar: YESPlanar: YESBenzene is aromatic!

129e pp 459–461

Cyclobutadiene

Electrons:A ti 4 2 ( ?)Aromatic 4n+2 (n=?)Anti‐aromatic 4n (n=?)

Cyclic:Cyclic:

Conjugated:

Planar:Planar:

139e pp 459–461

C lCyclooctatetraene

Cyclic:Cyclic:

Conjugated:

Planar:Planar:

149e pp 459–461

Ions: Aromatic or Anti‐Aromatic?

Cyclopentadienylanion

Cyclic:Cyclic:

Conjugated:

Planar:Planar:

159e pp 461–463

Ions: Aromatic or Anti‐Aromatic?

Cycloheptatrienyly p ycation

Cyclic:Cyclic:

Conjugated:

Planar:Planar:

169e pp 461–463

Heterocyclic Compounds

Heteroatoms can also contribute electrons:

Is pyrrole basic?

But in some cases, they do not:Is pyridine basic?

179e pp 464–465

Heterocyclic Compounds

Some aromatic compounds contain a heteroatom within the ring and are called heterocycles:

189e pp 464–468

Chemistry Connections

Quinine

• Contains an aromatic quinoline heterocycleHO N

O • Medical properties include anti‐pyretic (fever reducing) antimalarial analgesic

N(fever reducing), antimalarial, analgesic (painkiller) and anti‐inflammatory

• Traditionally used in tea but is also• Traditionally used in tea, but is also found in tonic water

• Extended conjugation gives rise to fluorescence under ultraviolet (UV) light

Isolated from the cinchona treeunder ultraviolet (UV) light

Take‐Home Activity

Circle the heteroatoms that contribute a lone pair of electrons to the ring to achieve aromaticity:g y

Name the following compounds as either aromatic, anti‐aromatic or non‐aromatic:

Draw structures for the following compound names:

Draw structures for

ng compound names:

Draw structures for

ng compound names:

Benzene vs. Alkene ReactivityThe aromatic stabilization of benzene has two effects on its reactions with electrophiles:1. It reacts more slowly than typical alkenes;2. Substitution, rather than addition, is observed (restores aromaticity)2. Substitution, rather than addition, is observed (restores aromaticity)

239e pp 479–481

Electrophilic Aromatic Substitution (SEAr or EAS)

f h h d h i i iOne of the hydrogen atoms on the aromatic ring is substituted with another functional group:

249e pp 479–481

SEAr Mechanism

Mechanism involves 2 steps:Mechanism involves 2 steps:

1. Addition of a “super‐hot” electrophile and formation of a hexadienyl cation intermediate (rate determining step)hexadienyl cation intermediate (rate determining step)

2. Deprotonation to restore aromaticity

259e pp 479–481

SEAr Reaction Energy Diagram

A large activation energy barrier must be overcome to produceA large activation energy barrier must be overcome to produce the carbocation intermediate. This is why the reaction requires a “super‐hot” electrophile!

A ti it i t d i th d t d th llAromaticity is regenerated in the product and the overall reaction is exergonic.

269e pp 479–481

What is a “Super‐Hot” Electrophile?

When a typical electrophile is activated by a Lewis acid (FeX3, AlX3) or a protic acid (H2SO4), a very reactive electrophile is generated:

279e pp 479–481

Halogenation with Br2 and Cl2

Chlorination and bromination work in the same manner:Chlorination and bromination work in the same manner:

• Generating the electrophile:

• Reaction:

‐ Fluorination generally requires specialized reagents (F is a highly reactive toxic gas);(F2 is a highly reactive, toxic gas);

‐ I2 is unreactive but can be activated by oxidation to I+289e pp 479–481; 482–484

H h idi

Chemistry Connections

Hypothyroidism

• Thyroxine is responsible for regulating thefor regulating the metabolism of fats, carbohydrates and proteins

• It is produced in the thyroid gland from tyrosine and iodine involving an SEArreaction with the iodonium cation:

• Thyroxine can be taken orally in cases of hypothyroidismof hypothyroidism

Nitration

Generating the electrophile:

Reaction:Reaction:

309e pp 484–485

Sulfonation

Reaction:

319e pp 485–486

Functional Group Reactivity

Groups introduced by SEAr can be subject to further chemical transformations.1 Sulfonation is reversible depending on the acid concentration:1. Sulfonation is reversible depending on the acid concentration:

2 Aromatic nitro groups can be reduced to anilines:2. Aromatic nitro groups can be reduced to anilines:

329e pp 485–486

The Friedel‐Crafts Reactions

The Friedel Crafts reactions are very important transformationsThe Friedel‐Crafts reactions are very important transformations where new C‐C bonds are made:

Charles Crafts and James Friedel in 1877

339e pp 488–492

The Friedel‐Crafts Alkylation

Aromatic compounds can be alkylated when treated with an alkyl halide and a Lewis acid (ex. AlCl3):

Reaction:

349e pp 488–492

1 Only alkyl halides can be used

Friedel‐Crafts Alkylation Considerations

1. Only alkyl halides can be used

Alkyl halide Aryl and vinyl halides are not reactive (cations are too high in energy)

2. Polyalkylation is a problem

359e pp 488–492

3 Carbocation rearrangement

3. Carbocation rearrangement

This leads to mixtures of isomeric products:This leads to mixtures of isomeric products:

369e pp 488–492

4 F i l i ibili

4. Functional group incompatibility

Alkylation will not occur if the aromatic substrate already has a strong electron‐withdrawing group:strong electron withdrawing group:

Basic amino groups become deactivators with Lewis acids:

379e pp 488–492

The Friedel‐Crafts Acylation

Aromatic compounds can be acylated when treated with an acid halide and a Lewis acid (ex. AlCl3):

Reaction:

*R group must be carbon!*389e pp 488–492

Friedel‐Crafts Acylation Considerations

1. No acylium cation rearrangement (unlike carbocations in F‐C alkylation):

2 Polyacylation does not occur (acyl groups deactivate)2. Polyacylation does not occur (acyl groups deactivate)

3. Functional group incompatibility is still an issue!

399e pp 488–492

Alkyl/aryl substituents can be converted to other useful groupsAlkyl/aryl substituents can be converted to other useful groups.

1. Bromination reactions (radical mechanism) can occur at the benzylic position as long as it has a benzylic hydrogen:benzylic position as long as it has a benzylic hydrogen:

409e pp 511–512

(Br source)

2 Alkyl and vinyl groups can be oxidized (via radical mechanism)2. Alkyl and vinyl groups can be oxidized (via radical mechanism) to a carboxylic acid as long as it has a benzylic hydrogen:

3. Aryl ketones can be reduced to alkyl groups:

419e pp 510–511; 513–514

In‐Class Activity

Predict the products of the following reactions:Predict the products of the following reactions:

Propose a synthesis of aniline from benzene:

The following reactions do not product the desired product (either g p p (at all or in poor yield). Describe why:

H ld k hi d l i l f b ?

How would you make this compound selectively from benzene?

Substituent Effects

Substituents on the aromatic ring affect the S Ar in two ways:Substituents on the aromatic ring affect the SEAr in two ways:

1. Rate of Reactivity

• Activating groups (electron donors) increase the rate • Deactivating group (electron withdrawing) decrease the rate

459e pp 493–495

Substituent Effects

2 Orientation (regioselectivity)2. Orientation (regioselectivity)

Three possible positions:Three possible positions:

metapara

Why don’t we see SEAr at the ipso carbon (carbon attached to R)?

469e pp 493–495

Substituent Effects

• Electron donating groups: activators that direct ortho/paraElectron donating groups: activators that direct ortho/para

• Electron withdrawing groups: deactivators that direct meta

• Halogens: deactivators that direct ortho/paraHalogens: deactivators that direct ortho/para

479e pp 493–495

Activating and Deactivating GroupsActivating groups stabilize the carbocation intermediate by g g p ydonating electron density to the aromatic ring

Deactivating groups destabilize the carbocation intermediate by withdrawing electron density away from the aromatic ring

489e pp 496–498

By the Hammond postulate, these substituents will stabilize / destabilize the transition states accordingly.

1 Induction: Electron withdrawing or donation effect

Inductive and Resonance Effects

1. Induction: Electron withdrawing or donation effect through a ‐bond due to electronegativity

Atoms or groups that are more electronegative than carbon withdraw electron density, while alkyl groups are slightly donating:donating:

Halogens (‐acceptor) Alkyl Groups (‐donor)

499e pp 496–498

2 Resonance: Electron withdrawing or donation effect

Inductive and Resonance Effects

2. Resonance: Electron withdrawing or donation effect through a π‐bond due to the overlap of p‐orbitals

EDG (π‐donor):EDG (π donor):

EWG (π‐acceptor):

Where are the most nucleophilic sites?

509e pp 496–498

Electron Donating Groups: Activating and Ortho/Para Directing

519e pp 499–500

Electron Withdrawing Groups: Deactivating and Meta Directing

529e p 502

Halogens: Deactivating and Ortho/Para Directing

Influence on rate reflects inductive effect (withdrawing)

539e p 501

Influence on rate reflects inductive effect (withdrawing)Influence on regioselectivity reflects resonance effect (donating)

Summary of Substituent Effects

549e p 503

Multiple SubstitutionSometimes, the effects of two substituents on regioselectivity, g yare reinforcing. If not, the more powerful activating group usually has the dominant effect. Steric effects may also influence the outcomeinfluence the outcome.

559e pp 503–504

In‐Class Activity

Complete the following multi‐step synthesis:

Predict the product of the following reaction:Predict the product of the following reaction:

Complete the synthesis:Complete the synthesis:

Nucleophilic Aromatic Substitution

Aryl halides with ortho and para electron withdrawing groupsAryl halides with ortho and para electron withdrawing groups are very electron poor and can react with nucleophiles:

589e pp 505–508

1 Attack of nucleophile at Cl‐substituted carbon (must have strong

Mechanism

1. Attack of nucleophile at Cl substituted carbon (must have strong EWG ortho or para to provide resonance stabilization)

2 Loss of halide to restore aromaticity2. Loss of halide to restore aromaticity

599e pp 505–508

Aromatic Substitution via Benzyne

When aryl halides are treated with base under high temperatureWhen aryl halides are treated with base under high temperature and pressure, benzyne is formed and attacked by nucleophiles.

• Distorted alkyne has 2 sp2‐C Benzyne:

(not the sp like typical alkynes).• 1 σ‐bond, 1 ‐bond and 1 weak

sp2–sp2 “bond”

sp sp bond .

9e pp 508–510

Using Benzyne to Make Phenols and Anilines

619e pp 508–510

Take Home Activity

Predict the following structures/reagents in the series:

A OH 1. NaOH

2. CH3BrCl

B2. CH3Br AlCl3

HNO3H SO

Pd/CGF

Take Home Activity

Write the mechanism of the following reaction to rationalize the products formed and to determine the ratio of products:p p

Aromaticity & Aromatic Substitution Reactions · PDF fileBenzene and Aromaticity...

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