electrophilic aromatic substitution

electrophilic aromatic substitution shortening

S_EAr (sub electrophil arom)

bromination of benzene

• overall equation including reagents and conditions

• mechanism and why it happens this way

• speed of steps in mechanism

mechanism = S_EAr

energy profile for bromination of benzene

slowest step = highest energy barrier

nitration of benzene

• overall equation including reagents and conditions

• ion needed and how it is formed

• mechanism, explanation and names of steps

nitric acid structure

HNO₃

sulfuric acid structure

H₂SO₄

sulfonation of benzene

• overall equation including reagents and conditions

• mechanism, explanation and names of steps

friedel-crafts acylation

• overall reaction including reagents and conditions

• mechanism and steps

friedel-crafts alkylation

• tertiary alkylation

• secondary alkylation

• primary alkylation

the primary alkylation is not friedel-crafts alkylation but is used as a workaround because primary alkyl chlorides result in rearrangement to secondary carbocations and hence secondary alkylation

names and positions for benzene substituents

referred to as ortho, meta and para relative to substituent X

ipso is the carbon with substituent X attached

effect on S_EAr if X is EDG

S_EAr reactions will

• be faster than for benzene

• happen preferentially at ortho or para

effect is X is EWG

S_EAr reactions will

• be slower than for benzene

• happen preferentially at meta

lower chemical shift = ?

• more shielding

• more electron density

• more nucleophilic

phenol resonance forms

where does electrophilic attack occur

at carbon with highest electron density - chemical shift is used as a measure

effect of electron density on rate

more electron rich aromatics will react faster than benzene

when does activation by resonance occur

mesomeric electron donation

when does deactivation by resonance occur

mesomeric electron withdrawal

resonance of nitrobenzene

order of chemical shifts for o/m/p for activation by resonance

order of chemical shifts for o/m/p for deactivation by resonance

deactivated in terms of electrophilic aromatic substitution

meta is least deactivated

effect of positive charges on activation

a positive charge deactivates a position as electron density is significantly reduced and the electrophile attacks the carbon with the highest electron density

activation by induction

• groups

• strength

• position (s)

• alkyl groups cannot participate in resonance but they can activate by induction (σ donors)

• weak activation

• ortho/para directing

deactivation by induction

• groups

• strength

• position(s)

• EWGs eg -CF₃, -NR₃⁺ can deactivate by induction

• strong deactivation

• meta directing

effect of EDG on resonance

position(s) preferred

stabilise the positive charge on the ipso carbon

ortho/para substitution favoured

effect of EWG on resonance

position(s)

destabilise positive charge on ipso carbon so meta substitution favoured so that this doesn’t happen

halogen effects

deactivating by induction

ortho/para directing due to weak resonance effects

relative rates of reaction for halogen substituents

why?

F > I > Cl > Br

due to electronegativity alone the order would be I > Br > Cl > F (as more deactivating the stronger the inductive effect) but the order is also affected by how good the resonance effects are

F’s lone pairs overlap best with the benzene pi-system due to the similar size of F and C 2p orbitals so F is more efficient at electron donation by resonance. I then has next best overlap as the 5p orbitals are not as tightly held as Cl’s 3p and Br’s 4p

N vs Cl

• similar electronegativity - both should deactivate by induction

• N has better orbital overlap than Cl for lone pair donation

• nitrogen is activating by resonance

• Cl is still o/p directing and is overall deactivating

compare the effects on reactivity (fastest → slowest) for:

• EDGs

• EWGs

• H

• halogens

• mesomeric EDGs

1. mesomeric EDGs

2. EDGs

3. H

4. halogens

5. EWGs

what is chemoselectivity

which functional group in a molecule reacts

reaction of phenol

• chemoselectivity

• rate compared to benzene

• can react at carbon or oxygen depending on the electrophile

• phenol is 10⁹ times more reactive

reaction of phenol with Br₂

reagents/conditions?

NaOH

reagents/conditions for step 1

resonance for step 2

curly arrows/reagents/conditions

2 possibilities and rate profile for reaction of carbon dioxide with phenol

• fast, reversible reaction with phenolate oxygen

• slower, irreversible reaction at ortho-carbon

aniline

reactivity of aniline with demonstrating reaction

• 10¹⁴ times more reactive than benzene

• forms tribromide product with benzene even in absence of Lewis acid catalyst

reagents/conditions

how is the reactivity of aniline controlled

why might this be done

• acetylation of the amine reduces its electron donation into the aromatic ring

• it also creates steric hindrance around the ortho positions

• can then create a monobromide rather than tribromide

reagents/conditions

Ac₂O

reagents/conditions

reagents/conditions

steric hindrance of acylated aniline

consequence

hinders ortho so mainly para-directing

how to control number of substitutions on a benzene ring

introduce a deactivating group allows clean mono-substitution

how to stop benzene substitution at mono (what introduced and where, reagensts/conditions)

B less reactive than A

effect of activating groups on substitution

• introducing an activating group encourages multiple substitutions

• when there are multiple activating groups, the strongest activator determines which position reacts next

how can activating groups be introduced

mechanism + reagents/conditions

how many groups?

• alkylation reactions introduce additional activating groups

• further alkylations will occur until steric factors prevent additional reaction

how to get monoalkylation

• use friedel-crafts acylation and reduction

• introducing an acyl group deactivates the ring (due to conjugation pulling electron density out of the ring), reducing the likelihood of further substitution

• clemmensen reduction allows conversion to alkyl group

which ring is more reactive

which positions are most reactive

ring on right more reactive - extra EDG, Me weakly activating

most reactive positions are ortho positions on the right ring

which ring is more reactive

Me weakly activating but NO₂ strongly deactiviating so ring on left more reactive

where will further nitration take place

para on left ring - least sterically hindered

problem of meta-bromination of phenol: what the problem is and how to solve it

• OH strongly o/p directing so cannot directly brominate at the meta position

• solution is to use a nitro-group as a latent hydroxyl group

reagents/conditions

why does Br attach there

reagents/conditions

reagents/conditions

type of product

reagents/conditions

NaNO₂ → diazonium ion on benzene ring

reagents/conditions

draw curly arrows/give reagents/conditions for next step

draw curly arrows

draw curly arrows

draw curly arrows

draw curly arrows

what is the product

diazonium ion - nitrogen leaving group

reaction of diazonium ions with Nu and conditions

at > 5ºC, N₂ leaves which leaves an empty sp² orbital which a nucleophile can attack

formation of phenol

+H₂O

formation of iodobenzene

+KI

formation of X-benzene where X = Cl, Br, CN

+CuX

formation of benzene

+hypophosphorous acid

formation of fluorobenzene from diazonium ion

add HBF₄ then follows mechanism

problem of meta-bromination of toluene: what is it + how to solve

• Me is o/p directing so not possible to directly brominate at the meta position

• solution is to temporarily introduce a stronger directing group

toluene → meta-bromotoluene

reagents/conditions

why steps done and how it helps the problem

1 - nitration

2 - amine

3 - amide

amide wanted as it is strong o/p director so can add another atom at meta to Me (as this is ortho to amide)

reagents/conditions

AcOH

reagents/conditions

reagents/conditions

<5 degrees

reagents/conditions

heat

reactions of diazonium salts with nucleophiles

reaction of diazonium ions with phenol