Unit 2

Mechanism: Electrophilic aromatic substitution

Mechanism: bromination of benzene

What is the rate-limiting step of the bromination of benzene?

formation of the sigma complex is strongly endothermic

Acid oxidizing agent examples

nitric acid, chromic acid, concentrated sulfuric acid

Reaction: iodination of benzene

Nitronium ion

Mechanism: nitration of benzene

Product of sulfonation of benzene

arylsulfonic acids

Why is sulfur trioxide a strong electrophile

S=O bonds draw electron density from the sulfur atom

Fuming sulfuric acid

7% SO₃ in H₂SO₄

Mechanism: sulfonation of benzene

Mechanism: desulfonation

Why does tolune react 25x faster than benzene

methyl group is electron-donating which stabilizes the sigma complex

Activating group

a group that makes the aromatic ring more reactive, usually toward electrophilic aromatic substitution

Inductive effect

electron density is donated to the ring through the sigma bond making it more active

Understanding placement selectivity

draw resonance and consider the structures of the sigma complex

Ortho attack with an ortho, para director

Para attack with an ortho, para director

Meta attack with an ortho, para director

Why are alkoxy substituents activating

oxygen donates electron density to stabilize the transition state via the lone pair through resonance

resonance/pi donating

donates electron density through a pi bond in a resonance structure

What happens when an alkoxybenzene comes into contact with Br

quickly brominates. if Br is in excess, a tribromide is formed

Where does the extra resonance structure come from in alkoxy substituents on benzene?

the oxygen can be double bonded to the ring

How is benzene’s reactivity compared to nitrobenzene

nitrobenzene is 100,000 times less reactive

Why do meta directed reactions happen slower

the transition state requires more energy

What makes the nitro group deactivating

Nitrogen inductively withdraws electron density from the aromatic ring, making it less reactive to electrophiles

How are halogens deactivating but ortho, para directing

inductive withdrawal and resonance donation oppose each other, so when an electrophile reacts at the ortho or para position the positive charge of the sigma complex is shared by the carbon atom bearing the halogen

Summary of electrophilic aromatic substituent effects on reactivity and positioning

When there is a conflict between activating and deactivating groups, how will reactivity be affected

activating group will direct because they are usually stronger directors

How to predict substitution products for compounds with more than one ring

decide which ring is more activated or less deactivated, then find the most reactive positions on that ring

Mechanism: Friedel-Crafts alkylation

Sources of carbocations that can be used in Friedel-crafts alkylation

protonation of alkenes by H₂SO₄, treatment of alcohols with BF₃,

Mechanism: carbocation formation from alcohols and BF₃

Limitations of Friedel-Crafts alkylation

does not work with deactivated systems, carbocation rearrangements can occur, multiple alkylations may occur

Minimum reactivity of Freidel-Crafts alkylation

halobenzene

How can multiple alkylations be avoided in Friedel-Crafts alkylation

excess of benzene

Acyl group

carbonyl with an alkyl group attached

Acyl chloride formation

reacting carboxylic acids with thionyl chloride

Mechanism: Friedel-crafts acylation

Why must water be added to Friedel-Crafts acylation

AlCl₃ complexes with the ketone part of the acylbenzene, water hydrolyzes it to give the free acylbenzene

Reaction: Clemmensen reduction

Hydrazine

What kind of substituents activate a ring toward nucleophilic attack

withdrawing groups

Mechanism: nucleophilic aromatic substitution

Benzylic position

alpha position of a side chain

Mechanism: side-chain halogenation

Selectivities of bromine and chlorine in side-chain halogenation

Br reacts exclusively at benzylic positions while Cl causes mixtures of isomers with a preference for the alpha position

Use of cross-coupling chemistry

substitute organic groups for halogens on aromatic rings or in alkenes

Reaction: making an organolithium reagent

Reaction: making a Gilman reagent

Reaction: cross-coupling with Gilman

Mechanism: Suzuki reaction

Stereochemistry of the Heck reaction

trans

Reaction: Heck reaction

What bonds generally break during phenol reactions

O-H bond, not the C-O bond

Why are phenols highly reactive

lone pair on the hydroxyl group stabilizes the sigma complex

How are phenoxide ions generated

treating a phenol with NaOH

How does the order of substitution determine products

to produce the ortho or para product, attach that director first. to produce the meta product, add that director first

How to add COOH to benzene

adding an alkyl group and oxidizing it

How does SO₃ work as a blocking group

blocks the para position so that substitution can occur on the ortho positions

structure of the carbonyl group

coplanar sigma bonds are about 120 degrees apart and the unhybridized p orbital overlaps with the p orbital of oxygen to form a pi bond

Energy of ketone double bond

745 kj/mol

Energy of aldehyde double bond

611 kJ/mol

Polarity of carbonyls

3 debeye

Acetone

simple ketone with two methyl groups

H bonding behavior of carbonyl compounds

can accept H bonds but cannot form them with each other

Formaldehyde

Acetaldehyde

IR spectroscopy of ketones

strong C=O at 1710

IR spectroscopy of aldehydes

C=O at 1725, C-H around 2710 and 2810

Formyl proton

proton attached to the carbonyl carbon on an aldehyde

How does conjugation affect IR spectroscopy of ketones and aldehydes

lowers it to around 1685 because partial pi bonding character on the single bonds reduces electron density on the carbonyl pi bond

¹H NMR of ketones and aldehydes

characteristic formyl protons around 9-10, alpha carbon protons around 2.1-2.4

¹³C NMR of ketones and aldehydes

carbonyl carbon around 200, alpha carbon around 30-40

Common fragmentation patterns of ketones and aldehydes

loss of alkyl group to give an acylium ion, McLafferty rearrangement

McLafferty rearrangement

a cyclic intramolecular transfer of a hydrogen atom from the gamma carbon to the carbonyl oxygen that is equivalent to a cleavage between the carbon atoms alpha and beta to the carbonyl group plus the transfer of a beta hydrogen to the oxygen

reagent for the oxidation of secondary alcohols to ketones and aldehydes

Jones reagent: chromium trioxide in sulfuric acid

How to use primary alcohols to make ketones and aldehydes

NaOCl + TEMPO or pyridinium chlorochromate

Pyridinium chlorochromate

Ozonolysis of alkenes

creates ketones and aldehydes when the double bond is oxidatively cleaved by ozone followed by reduction

Use of DMS

protects the aldehyde in ozonolysis

Hydration of alkynes by acid and mercuric salts

initial product is an enol which tautomerizes to its keto form, catalyzed by sulfuric acid and a mercuric ion

Sia₂BH

reagent used in hydroboration-oxidation of alkynes to form an anti-markovnikov aldehyde

Reaction: organolithium reagent with carboxylic acid

Mechanism: synthesis of ketones from nitriles

Reaction: reduction of nitriles to aldehydes

Acid chloride

reactive derivative of carboxylic acids in which the hydroxyl group is replaced by Cl

Reaction: synthesis of acid chlorides

Reaction: reduction of acid chlorides

Reaction: reduction of esters

Grignard/organolithium reaction with acid chlorides

add an R group, gives a tertiary alcohol

Reaction: formation of Gilman reagents

Reaction: Gilman and acid chloride

Why are aldehydes more reactive than ketones to nucleophilic addition

more electron poor, more exposed toward attack

Mechanism: nucleophilic addition in basic conditions

Mechanism: nucleophilic addition in acidic conditions

Why are aldehydes more likely to form stable hydrates than ketones

ketone carbonyl is stabilized by two alkyl groups

K_eq of a ketone in aqueous solution

10^-4 to 10^-2

K_eq of aldehyde in aqueous solution

~1