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
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My contact info:
Prof. Mitch Winnik
Office hours: Thursdays 2 4 PMOffice hours: Thursdays 2–4 PM
Office: LM520 (fifth floor, Lash Miller building, 80 St. George St.)
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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)
CH3
OH
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:
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3
3
21
3
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:
IR
Aromatic 1H: δ 6.5–8.0 ppm Aromatic 13C: δ 110–175 ppm
IR
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
Aromatic, Anti‐Aromatic or Non‐Aromatic?
Cyclobutadiene
Electrons:A ti 4 2 ( ?)Aromatic 4n+2 (n=?)Anti‐aromatic 4n (n=?)
Cyclic:Cyclic:
Conjugated:
Planar:Planar:
139e pp 459–461
Aromatic, Anti‐Aromatic or Non‐Aromatic?
C lCyclooctatetraene
Electrons:A ti 4 2 ( ?)Aromatic 4n+2 (n=?)Anti‐aromatic 4n (n=?)
Cyclic:Cyclic:
Conjugated:
Planar:Planar:
149e pp 459–461
Ions: Aromatic or Anti‐Aromatic?
Cyclopentadienylanion
Electrons:A ti 4 2 ( ?)Aromatic 4n+2 (n=?)Anti‐aromatic 4n (n=?)
Cyclic:Cyclic:
Conjugated:
Planar:Planar:
159e pp 461–463
Ions: Aromatic or Anti‐Aromatic?
Cycloheptatrienyly p ycation
Electrons:A ti 4 2 ( ?)Aromatic 4n+2 (n=?)Anti‐aromatic 4n (n=?)
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
HO NH
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
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Take‐Home Activity
Circle the heteroatoms that contribute a lone pair of electrons to the ring to achieve aromaticity:g y
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Take‐Home Activity
Name the following compounds as either aromatic, anti‐aromatic or non‐aromatic:
N ON
N
O
HN O
NH
N
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Take‐Home Activity
Draw structures for the following compound names:
Draw structures for
ng compound names:
Draw structures for
ng compound names:
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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:
3 3
4
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
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Nitration
Generating the electrophile:
Reaction:Reaction:
309e pp 484–485
Sulfonation
Generating the electrophile:
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):
Generating the electrophile:
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
Friedel‐Crafts Alkylation Considerations
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
Friedel‐Crafts Alkylation Considerations
4. Functional group incompatibility
Alkylation will not occur if the aromatic substrate already has a strong electron‐withdrawing group:strong electron withdrawing group:
Y Y
3
Basic amino groups become deactivators with Lewis acids:
3
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):
Generating the electrophile:
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
Functional Group Reactivity
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)
Functional Group Reactivity
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:
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Propose a synthesis of aniline from benzene:
Take‐Home Activity
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:
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H ld k hi d l i l f b ?
Take‐Home Activity
How would you make this compound selectively from benzene?
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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:
ortho
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:
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Take‐Home Activity
Complete the synthesis:Complete the synthesis:
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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”
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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
AlCl
O
B2. CH3Br AlCl3
HNO3H SO
B
H2SO4
C+D
E
Br2
FeBr3
H2
Pd/CGF
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Take Home Activity
Write the mechanism of the following reaction to rationalize the products formed and to determine the ratio of products:p p
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