Thẻ ghi nhớ: UBC Chem 213 Chapter 22 | Quizlet

What is the overall generic reaction for the electrophilic aromatic substitution?

Ph + E⁺ → PhE + H⁺

Electrophile is on the ring, a proton has been lost.

What types of reactions does the electrophilic aromatic substitution apply to? (5)

Halogenation, nitration, sulfonation, alkylation, acylation.

What is the generic process of electrophilic aromatic substitution?

Aromaticity is broken and resonance stabilized cationic intermediate is formed.

What is the effect of electron-donating groups on the electrophilic aromatic substitution?

They enhance substitution at ortho and para positions.

What is the effect of electron-withdrawing groups on the electrophilic aromatic substitution?

They retard substitution, especially at ortho and para positions.

How is nitrate formed?

HN⁺O⁻₃ + H₂SO₄ → N⁺O₂ + H₂O + HSO₃⁻

What is the mechanism of nitration?

Pi-electron on the benzene ring attacks the N of the nitrate (since it is positive). Carbocation is formed on the benzene ring, it becomes non-aromatic, but resonance-stabilized. HSO₃ in the solution picks up the proton on the other side of the broken pi-bond and the bond is recreated, aromaticity re-established.

What are anilines?

Ph-NH₂

Can anilines be nitrated directly?

No, since it is a strong electron-withdrawing group. Meta-directing.

Since the solution is protonated with a strong acid, NH₂ will get protonated which will make it even more electron withdrawing and hence non-reactive.

Meta position

one CH between two groups.

How to nitrate anilines?

1) Acylate the NH₂ group to protect it: use acid halide or anhydride.

2) protonate, perform nitration. The nitrate will attach to either ortho or para position due to the presence of at least some electron density.

3) Deprotect with mild H₃O⁺ or aq. KOH.

NH₂-Ph + H₂SO₄

NH₃⁺-Ph, non-reactive, super electron withdrawing.

NH₂-Ph + Acid halide

CH₃-C(=O)-NH-Ph. Can be nitrated at ortho/para positions.

Why can nitro group reduction be useful?

NH₂ is more electron donating than NO₂ - can be seen as sort of activation.

NO₂-Ph + Zn/HCl or H₂/Pd or (NH₄)₂S

NH₂-Ph (reduction reaction)

What are the reducing agents that could work with phenyl nitriles?

Zn/HCl

H₂/Pd

(NH₄)₂S

What comopound does sulfonation of benzene result in?

SO₃H-Ph + H⁺

What is the key reactant of sulfonation?

SO₃ ~30% in concentrated H₂SO₄

What is the mechanism of sulfonation?

Basically the same as the mechanism of nitration: the aromaticity is broken when the pi electrons attack SO₃, cation is formed, H⁺ is removed to restore aromaticity.

What compounds does halogenation work with?

Cl, Br, but not F (since it is too reactive)

How does halogenation of benzene work?

1) X₂ + X₃Fe → X⁺ + X₄Fe⁻

2) X⁺ + Ph → Cyclohexadienyl cation

3) X₄Fe⁻ + cyclohexadienyl cation → rearromatized halobenzene + HFeX₄

4) HFeX₄ + X⁻ → HX + FeX₃

What are some of the electron withdrawing groups? (list 7)

NO₂, CN, CF₃, COOMe, C=O, NH₃⁺, SO₃

What are some of the electron donating groups? (List 8)

Alkyl, aryl, OH, OR, NHR, N-amide, SR, SH.

At what positions and how do the EWGs effect electrophilic substitution reactions?

They retard the reactions at all the positions, but especially strong at ortho and para positions.

What effect do the electron donating groups have on the electrophilic substitution reactions?

They increase the rate of electrophilic substitution at ortho/para positions and retard it at meta-position.

What effect do halogens have on electrophilic substitution reactions?

Deactivate the electrophilic substitution in general, more so at the meta-position than ortho/para. Hence, ensure ortho/para substitution, but at lower rates.

Anisole

Methoxybenzene: CH₃O-Ph

E⁺ + anisole

C=O:-CH₃ in ortho position with E, the carbocation sits on oxygen due to the fact that oxygen is so highly electron donating and just gives off the electrons into the pi-system.

Why are halogens ortho/para directing?

Because they stabilize carbocations adjacent to them, which permits the ortho/para substitution even though they usually are electron-withdrawing. Charge sits on the halogen, C=X⁺.

Why is meta-substitution disfavoured for halobenzenes?

Halonium ion resonance structure would not be there.

Why are EWGs meta-directing?

E.g. NO₂: Nitro group already has a positive charge. In order to favor ortho/para substitution, the cation should be right next to this group, but it would result in charge repulsion.

How does halogenation work with electron-donating group-containing aryls?

No catalyst is needed, the reaction spontaneously goes to ortho/para positions.

Friedel-Crafts alkylation

Strong electrohpile is created to add an alkyl group to the benzene.

What are alkylating agents for Friedel-Crafts alkylation and how do they work? (list 4)

FeBr₃, AlCl₃, FeCl₃, AlBr₃: they act as strong halo/oxophilic Lewis acids to create a strong electrophile.

Sometimes a strong acid might work as well.

What alkanes/alekenes does Friedel-Crafts acylation work with?

R-CH₂-Br-FeBr₃ (where FeBr₃ holds partial negative charge, Br holds partial positive charge and CH₂ is thus likely to be attacked by the pi-bond).

R can be either methyl or hydrogen.

Friedel-Crafts acylation also works well with 2° and 3° bromides.

What alkanes/alkenes does Friedel-Crafts acylation not work with?

Vinyl and aromatic halides since cations are unstable

If a long or branched primary halide is used in Friedel-Crafts acylation - what happens?

Hydride might migrate, following the hydride, the bromide would migrate and branching would occur. Stabilization of carbocation is the main driving force and Br might pick up the hydrogen to form double bond at beta-position, which would result in bond migration.

What is the final product of over-alkylation?

1,3,5-substituted product.

What is an exception to over-alkylation? Only 2 possible products formed.

1-benzyl-4-halobutane + AlCl₃ → tetralin (major product) + methylindane (minor product).

How to prepare Friedel-Crafts agents from alcohols and vinylic alkenes?

Use a strong inorganic acid, such as H₂SO₄, H₃PO₄, HClO₄: counterion should be non-nucleophilic.

How does Friedel-Crafts acylation work with aldehydes/ketones?

1) C=O---BF₃: benzene attacks the C from behind, One electron pair from the C=O bond moves to make a bond with BF₃; resonance-stabilized cation is formed.

2) H at the bond with the new substitute is released to rearromatize the compound.

3) if vigorous anhydrous conditions are created, OBF₃ is removed and C=C is created instead. If low temperatures and/or aqueous/acidic conditions can be used, tertiary/secondary alcohol can be obtained.

Ketone + BF₃ + benzene (vigorous anhydrous conditions)

Dehydrated product: Ph-CR=CH-R

Friedel-Crafts acylation with ketones

Ketone + BF₃ + benzene (low temperature, aq./acidic work-up)

Tertiary alcohol: Ph-CR(OH)-CH₂R

Aldehyde + BF₃ + benzene (vigorous anhydrous conditions)

Ph-CH=CH-R

Aldehyde + BF₃ + benzene (Low temperature, aqueous/acidic work up)

Ph-CH(OH)-CH₂R

What are the limitations of Friedel-Crafts Alkylation/acylation?

1) Does not work with EWG-substituted benzenes. Too deactivated. (can work with double EWG/EDG substituted benzenes if one of the substituents is strongly EDG)

2) Anilines don't work since they complex with the metal catalysts. To protect, must be acylated with an acyl-halide or anhydride.

If you have a nitrobenzene, is it possible to perform Friedel-Crafts acylation?

No - too electron withdrawing!

If you have an aniline, is it possible to perform a direct Friedel-Crafts acylation/alkylation on it?

No, it would complex with the metal catalysts. To perform the reaction, protect them by acylating with anhydrides or acid halides.

What is Friedel-Crafts acylation done with?

Acid halide!

How does Friedel-Crafts acylation work?

1) Acid halide complexes with AlCl₃ or FeCl₃ or one of the two other catalysts.

2) Cl-MX₃ is removed, O donates one electron pair to make an acylium ion (resonance stabilized).

3) pi-bond of benzene attacks the carbocation , another carbocation is formed, on the ring.

4) H donates an electron pair, leaves as H⁺, the ring is rearromatized. Ketone is formed.

Acid halide + MX₃ + Benzene

Phenyl ketone

How to get phenyl alkane from phenyl ketone?

Clemensen/Wolff-Kishner reduction.

What happens if electronically mismatched groups are substituting the benzene?

A mixture of products.

Does nitration and sulfonation work with EDG?

Yes, works under all conditions, can introduce up to 3 nitro groups (harder to introduce with each subsequent group). Anilines must be protected with acylation.

Does nitration and sulfonation work with EWG?

Yes, works under all conditions, can introduce up to 3 nitro groups (harder to introduce with each subsequent group). Anilines must be protected with acylation.

Does halogenation work with EDG?

Yes, para-halogenation dominates due to sterics. Often not clean if halogenating doubly substituted benzenes.

Aniline + NaNO₂ + HX

Ph-N=-N

Diazotization

Does halogenation work with EWG?

Yes, often not clean if halogenating doubly subsituted benzenes.

Does Friedel-Crafts alkylation work with EDG?

Yes: only on benzene and EDG modified aryls (even if EWGs are present).

Might overalkylate.

Phenols/anilines must first be acylated in order to protect the group.

Does Friedel-Crafts alkylation work with EWGs?

No

Does Friedel-Crafts acylation work with EDGs?

Yes, only on benzene and EDG-modified aryls. Phenols and anilines must be acylated first.

Does Friedel-Crafts acylation work with EWGs?

No.

Dazonium

Ph-N₂⁺. Highly electrophilic.

How to make diazonium?

1) Ph-NO₂ + Zn-HCl or H₂/Pd or (NH₄)₂S (reduction) →Ph-NH₂ (EWG to EDG)

2) Ph-NH₂ + HCl/HNO₂ → Ph-N₂⁺

Are aryldiazoniums stable?

Yes

Are alkyldiazoniums stable?

No, react upon heating with a nucleophile (I, Br, Cl, CN, N₃) typically in water.

What happens to the aryldiazonium?

N₂ leaves and leaves carbocation which is neutralized by nucleophile (SN1-like reaction)

Aryldiazonium + H₂O, ∆

Phenol

Aryldiazonium + K₂HPO₃

Benzene

Phosphite

K₂HPO₃

Ph-N₂⁺X⁻ + KNO₂

Ph-NO₂

Ph-N₂⁺X⁻ + KX (X = Cl, Br, I)

Ph-X

Ph-N₂⁺X⁻ + KN₃

Ph-N₃

Ph-N₂⁺X⁻ + KBF₄

Ph-F

Ph-N₂⁺X⁻ + K₂HPO₃

Benzene

Ph-N₂⁺X⁻ + CuCN or NaCN

Ph-CN

How to get phenol from Ph-N₂⁺X⁻?

Heat in water solution (or weak base)

How to get nitrobenzene from Ph-N₂⁺X⁻?

Add KNO₂

How to get halobenzene from Ph-N₂⁺X⁻?

Add KX

How to get phenyl azide from Ph-N₂⁺X⁻?

Add KN₃

How to get fluorobenzene from Ph-N₂⁺X⁻?

Add KBF₄

How to get benzene from Ph-N₂⁺X⁻?

Add K₂HPO₃

How to get benzonitrile from Ph-N₂⁺X⁻?

Add NaCN or CuCN

Ph-X + Nu:⁻ → ? (Nu:⁻ = HO⁻, RS⁻, N₃⁻, NC⁻)

No reaction.

What are the conditions for a successful nucleophilic aromatic substitution?

1) Need a leaving group

2) Need a good nucleophile

3) Need a strong EWG

What are good leaving groups for nucleophilic aromatic substitution?

F > Cl > Br ~ OTf > I (inverted from the standard SN2 leaving groups)

What are good nucleophiles for nucleophilic aromatic substitution?

amine, alkoxide, thiolate, CN, N₃, sulfide, hydroxide, enolate

What are good EWGs for nucleophilic aromatic substitution? Where?

Ortho/Para position. (pi-delocalizable off the ring) Classically NO₂, could be aldehyde or nitrile.

What role does an alkoxide play in nucleophilic aromatic substitution?

Nucleophile

What role does F play at nucleophilic aromatic substitution?

Leaving group

What role does NO₂ play at nucleophilic aromatic substitution?

EWG

What role could an aldehyde play for nucleophilic aromatic substitution?

EWG, but yields extensive side reactions.

What does Meisenheimer Salt look like?

Ph-1-Nu-1-X-4-NO₂⁻

Where from NO₂ does nucleophilic aromatic substitution usually take place?

Ortho/para position.

How does Hantzsch pyridine synthesis work?

1) Diketone (3C between) + NH₃/NH₄Cl → release of H₂O, one ketone group changed by NH₂⁺

2) Deprotonation

3) NH₂ attacks carbon of the second carbonyl. H₂O is released, primary pyridine is formed

4) Tautomerize to form 6-membered ring with NH and 2 C=C

5) Oxidize with I₂, Br₂ or in air to rearromatize

Diketone + NH₃/NH₄Cl

Pyridine

Skraup Quinoline synthesis

Glycerol + aniline (H₂SO₄) → [O] → Quinoline

Start with dehydration of glycerol and follow it with 1,4-Michael addition, then just cyclize.

Quinoline

Phenol and pyridine (double ring)

Bischler Indole synthesis

Aniline + 2-Bromo-1,1-dimethoxyethane, carbonate, then trifluoroacetic anhydride in triethylamine → Ph-N(-C(=O)-CF₃)-CH₂-CH-(OCH₃)₂ + F₃CCOOH with trace H₂O, ∆ → dehydrated ether to one C=O (possible intermediate) → cyclization to indole with C(=O)-CF₃ attached to N + KOH or NH₄OH → indole

Indole

Phenyl ring + pyrrole (without H on N)