1) Metal-Induced Radicals and Radical Reactions

What are three features of reactive intermediates?

• Species that are not isolated (transient species, normally low conc in reactions since at high concs a lot of side reactions will occur)

• Can be detected by spectroscopic methods, or trapped chemically

• Presence often confirmed indirectly through mechanistic understanding

What is a free radical?

Contains an unpaired e^-

• therefore electron deficient

• but normally uncharged

How do you form a radical (radical pair)?

By direct homolysis of a weak sigma bond

Bond order

BO = (bonding e^-s - antibonding e^-s)/2

Table of BDE

What’s a radical initiator?

Species to propagate desired chemical process - weak bonds which readily undergo thermolysis as precursors.

What are 2 features of a good thermally activated radical initiator?

• stable at room temperature for practicality

• rapidly fragment at a controlled rate under usable reaction temperatures (>60ºC → <150ºC

What is the decomposition rate and what is it dependent on

k_d predicts the rate of decomposition

Dependent on temperature and the solvent used

(If the radicals react with each other of the solvent then it is an unproductive reaction (the cage effect)) The cage effect causes unproductive “wastage” reactions including recombination of radicals to reform the initiator.

What is the initiator half life (t_1/2)

The time required for the reacting species to reduce to half its initial conc at a given temperature and in a particular solvent

What is the relationship between bond strength and half life?

Weaker bond = shorter half life

Relationship between temperature, k_d and t_1/2

higher temp = lower half life and higher k_d

Name three common radical initiators

Benzoyl peroxide

2',2’-azobisisobutyronitrile (AIBN)

tert-butyl hydroperoxide

Draw benzoyl peroxide and its homolysis

Draw AIBN and its homolysis

Draw tert-butyl hydroperoxide and its homolysis

What is another way to form radicals (other than weak bond homolysis)?

By single electron reduction or oxidation

(addition or removal of one e^-)

How can reductive metals produce radical anions?

• Reductive metals i.e. Li, Na, K and Mg are readily oxidised.

• They dissolve in certain solvents (like ammonia or alcohol)

• Can produce solvated e^-s that occupy pi orbitals (e.g. pi* of carbonyls or aromatics) → prod radical anions

Which metals are reductive and produce radical anions

Li, Na, K, and Mg

also known as the dissolving metal reduction process

What is the Birch reduction? Show the mechanism.

Reduction of arene to cyclic diene. Reagents: alkali metal, NH₃, EtOH and Et₂O

During dissolving metal reductions, where does an EDG sit in relation to the double bonds?

EDG always sits on the double bond

During dissolving metal reductions, where does an EWG sit in relation to the double bonds?

EWG avoids the double bond

e.g. withdraws = avoids (EWG sits between diene units)

How can Cu²⁺, Fe³⁺, Ce⁴⁺ be used to generate a radical cation?

They’re one electron oxidising agents

• used to remove an electron from high energy HOMO (pi orbitals of aromatics)

What are the three useful synthetic radical processes (excluding polymerisation)?

1) Radical Combination: union of 2 free radicals → new sigma bonded structure

2) Atom Abstraction: Typically radical attacks a H atom, forming a new radical species (displacement process)

3) Addition: The radical can add to a double bond. Regioselectivity is controlled by the resulting stability of the radical generated

What are simple alkyl radicals like?

Unstable, reactive and v short-lived,

Essentially electron poor species.

What are e- poor species stabilised by?

Stabilised by neighbouring atoms that can donate e- density (think CC stability and hyperconjugation of alkyl grps)

Also by resonance

What does radical stability depend on?

More substituted radicals are more stable due to electron donation and hyperconjugation

radicals can be stabilised by resonance

What is the SOMO? How do EWG and EDG differ with this?

Singly Occupied Molecular Orbital

Greater stabilisation energy for EDG radicals

• because LP contributing the the MO diagram → 2 electrons go down in E and one electron goes up in E.

• Overall ΔE = 2ΔE₁ - ΔE₂

What is the captodative effect?

Alkyl radicals very reactive. Can be stabilised by:

• delocalisation into pi systems e.g. allyl or benzyl

• adjacent EWG or EDG systems

• combo of these factors → further stabilisation

= captodative effect

How are radicals detected and why is detection hard?

Detected via e^- spin or paramagnetic resonance spectroscopy (ESR or EPR) - allow the study of unpaired electrons (to see if radical exists or not)

For CH₃ radical, the 3 Hs (spin active) give a 1:3:3:1 quartet

Detection hard because radicals have short half lives.

What is the pinacol coupling reaction?

Generates new covalent bond between 2 carbonyl units forming a 1,2-diol (pinacol)

Uses an M(0) metal such as Mg

Draw pinacol coupling reaction mechanism.

An electron on Mg attacks the O of a carbonyl which breaks to form a diradical. The radical on the Mg repeats on another carbonyl. The two radicals combine to form a bond. Mg is removed using acid hydrolysis.

What is the McMurray Reaction?

Combines two carbonyl species to form an alkene using low valent titanium (e.g. TiCl₃) and Na/Zn.

Low valent titanium can couple aldehydes and ketones to the corresponding alkenes

The low valent titanium species is prepared by the reduction of a TiXn species, where X is a halide, with K, Na, Li, Zn, Mg, C₈K, LiAlH₄ (electron donors)

How is TiCl3 reduced by Zn (to make a low valent titanium for McMurray reaction?)

Active [Ti] generated in presence of carbonyl species with zinc as reductant - instant method.

Zn donates its lone pair into the sigma* orbital on Ti-Cl, breaking one of the Ti-Cl bond and kicking a Cl out of the complex

Makes TiCl and Zn(+)Cl

The floating Cl- attacks the Zn+ to form TiCl and ZnCl2

What are the steps of the McMurray reaction? Show mechanism.

• Low valent Ti donates one electron to the carbonyl oxygen, forming Ti-O and breaking C=O

• Forms a free radical centre around the carbonyl

• Does it again for the other carbonyl

• 2 radicals come together to form a new sigma bond

• One electron on titanium goes into the Ti-O bond, along with an electron from the C-O bond. The other electron from the C-O bond goes onto the new sigma bond (exact same for the other site)

• The Ti-O bond is taken off and the new sigma bond is now a double bond

i.e. Ti+ radical attacks O of a carbonyl, breaking the bond to form a radical. This repeats and the two carbonyl radicals combine. The C-O bonds breaks to form an alkene and 2 TiClO

How can the McMurray reaction be improved? What are the benefits

Creating catalytic process. Reduces costs.

A replenishing species (Me₃SiCl) is introduced → allows low valent Ti species to reform and be reused.

Using 4 Me₃SiCl to oxidise 2 TiOCl back to 2 TiCl₃ to recover the catalyst, removing 2 (Me₃Si)₂O

What is the Acyloin reaction? Draw the mechanism.

Reductive coupling of esters (similar mechanism to pinacol reaction)

This converts two esters to an α-hydroxy ketone using Na

• Metal reduces carbonyl to form a radical

• Radical coupling to join two former carbonyls together

• Metal reduces carbonyls again

• Radical coupling to form a double bond

• Add H+ to form a dihydroxy

• Tautomerisation forms α-hydroxy ketones

Works v. well as intramolecular process.

How can HBr be added across a double bond to the least substituted carbon?

Using HBr through a radical process, activating using MeO-OMe (good radical initiator) and hν

(opposite regioselectivity to electrophilic addition)

What are the 4 stages of a radical chain reaction?

Homolysis (formation of the radicals)

H-abstraction

Addition to double bond (of free radical to other structure to form most stable radical)

H-abstraction

Latter steps representative of a reaction cycle so only require small amounts of the radical initiator to generate lots of product. Can present this reaction in a reaction cycle.

Show radical chain reaction cycle.

Why do you keep the concentration of the initiator low in a radical chain reaction?

Only 5-10%.

To minimise unproductive side reactions (some termination steps)

How can an allylic or benzylic hydrogen be substituted for a halogen (mainly Br, Cl and I)? Draw the mechanism.

Radical halogenation of an allylic or benzylic compound using N-halosuccinamides.

Homolysis of the initiator (halogen)

Halogen abstracts hydrogen (hydrogen abstraction) to form an allylic/ benzylic radical

This radical reacts with the halogen (e.g. Br₂) to create a halogen substituted allyl/ benzene and regenerates the radical (the chain carrier)

Can be represented in a cycle (not shown here).

What is the oxymercuration reaction and what are the initial steps?

A reaction that turns an alkene into an alcohol using HgCl₂ and NaBH₄.

1) Hg(II) salt coordinates to the alkene, making the alkene more electrophilic

2) OH then attacks the alkene, kicking out Cl.

Draw mechanism of oxymercuration reaction.

Rxn turns an alkene into an alcohol using HgCl₂ and NaBH₄.

1) Hg(II) salt coordinates to the alkene, making the alkene more electrophilic

2) OH then attacks the alkene, kicking out Cl.

3) Nucleophilic ligand exchange (NaBH₄ then replaces Cl with H. )

4) R-Hg sigma bond homolysis (initiation) to give radicals

5) Propagation (H abstraction of the H attached to the Hg of another molecule)

6) Hg removed

7) Termination

What is the benefit of knowing the radical involved?

Allows synthetic chemists to use the sequence to create more elaborate structures

How can a halogen be replaced by H?

What is used in a dehalogenation reaction?

Dehalogenation - radical substitution of C-X bonds

Bu₃SnH can be used to furnish a halogen-hydrogen exchange

Catalytic AIBN is used to initiate the radical-chain reaction (AIBN added slowly so does not quench R or react with the alkene instead)

What are Baldwin's Rules?

Used to name ring closures and used to determine if they are allowed

N-exo/endo-tet/trig/dig

N = number of atoms forming the ring (ring size)

exo = if the bond being broken is outside of the ring being formed

endo = if the bond being broken is part of the ring being formed

tet/ trig/ dig = hybridisation of the reaction centre

If sp3 hybridised = tet

If sp2 hybridised = trig

If sp hybridised = dig

Learn table to determine whether or not the cyclisation can actually occur

What are 4 features of a carbene

Neutral charge

Divalent (2 valence electrons)

Highly reactive carbon intermediates with short lifetimes

Exist in 2 different spin states: singlet and triplet

What is the difference between a singlet carbene and a triplet carbene

Singlet carbene:

Carbon is sp2 hybridised

The lone pair of electrons occupy the same p orbital

Can react in a concerted way

Triplet Carbene:

Carbon is sp hybridised

The lone pair of electrons occupy different orbitals

Most stable

Can be referred to as a diradical and react in a stepwise sequence

The different spin states react differently, forming different products

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What happens when a triplet carbene reacts with an alkene

One electron from the carbene reacts with one electron from the pi bond to form a diradical intermediate

C-C bond rotation occurs to get the unpaired electrons close together

Electron spin inversion occurs so the electrons can react

ring closure

IF rotation occurs before spin inversion, the trans product is made (inversion slower than bond rotation)

IF spin inversion occurs before bond rotation, the cis product is made (very fast spin inversion)

STEP WISE PROCESS

What happens when a singlet carbene reacts with a cis-alkene

Similar to a chelotropic reaction

Lone pair of electrons attack the emtpy pi star orbital of the C=C

The pair of electrons in the pi bond are offloaded into the empty p orbital of the carbene

Ring closure

CONCERTED PROCESS- Make and break bonds simultaneously

Only Cis product is formed

How is a carbene generated from an alpha-elimination reaction

React a chloroform with NaOH (chloroform = CCl3H)

OH- removes H to generate a carbanion

negative charge puts an electron pair into the empty chlorine p orbital

Forms a singlet dichlorocarbene

lone pair of electrons on the Cl form a stabilising bond interaction with the empty C p orbital

What is the product when an electron deficient carbene reacts with an electron rich alkene

formed strained three membered rings

attack of alkene electrons into the empty p orbital if the dichlorocarbene

What is the Reimer-Tieman reaction

The alpha-formylation of a phenol

Deprotonate a phenol to form an enolate

React with a singlet dichlorocarbene

deprotonate this structure to regenerate aromaticity and quench the negative charge of the C with water

lone pair of electrons on the O come back into form C=O, resulting in Cl being kicked out, to form an alkene branch

React with OH to eliminate the alkene and kick out the remaining Cl

Quench the product with HCl

Can get an ortho or para product

How do carbenes undergo a 1,2-shift

step wise process

lone pair has to be 90 degreed to the p orbital so rotation has to occur

What occurs during the Wolff rearrangement

allows a diazoketone to be transformed into a ketene

trapped by water or alcohol to form the corresponding carboxylic acid or ester

diazoketone has a resonance form, which includes a Nitrogen triple bond and a C-O (-)

Under hv, C=O reforms and N2 is kicked out to form a carbene

1,2 shift occurs in a step wise process to form a ketene

If this ketene reacts with a nucleophile (water, amines, alcohols), the corresponding carboxylic acid will form

What happens in the Wolff rearrangement if the diazoketone is cyclic

Results in a ring contraction e.g. 6 membered ring to a 5 membered ring

Same as before but the 1,2-alkyl shift is part of a ring system, which results in ring contraction

What is the Arndt-Eister synthesis

Used to prepare beta-amino acids from the more readily available equivalent alpha- amino acids

What is the Corey-Fuchs reaction

converts and aldehyde into an alkyne

1) formation of the ylid

React Ph3P with CBr4

React this ylid with an aldehyde

P(+) and O(-) react to form a cyclic structure with a P-O

Ring collapses due to the thermodynamic driving force of forming a P=O to form an alkene

react this alkene with Bu-Li,

Li substitutes a Br

Remaining Br is kicked off

Alpha-elimination produces a carbene

a 1,2-shift of the carbene results in the formation of an alkyne

What is the Seyferth-Gilbert homologation reaction

allows the direct transformation of an aldehyde into the corresponding alkyne

aldehydes form a mono-substituted alkyne

ketones form a disubstituted alkyne

MeOH attacks the C=O of the Ohira-Bestmann reagent, forming a good LG, so is then kicked out

The negative charge attacks an aldehyde at the C=O, forming a O(-)

O(-) attacks P to form a ring, which then collapses to form a P=O

the linear carbon nitrile undergoes alpha-elimination to form a carbene

carbene undergoes a 1,2 shift to form an alkyne

What are nitrenes

analogues if carbenes

nitrogen has 6 valence electrons

2 electrons involved in bonding

4 non-bonding electrons

can be a singlet (sp2 hybridised- electrons paired in 2 orbitals)

can be a triplet (sp hybridised- one electron in one orbital, one electron in another orbital, 2 electrons in another orbital)

Which state of nitrene is lower in energy

the triplet state is much lower in energy

what are the 4 methods of preparing nitrenes

1) elimination from azides (forms a triplet)

2) 1,1- elimination (forms a triplet nitrene)

3) via oxidation of a disubstituted hydrazine (forms a singlet since second N can stabilise the structure into an empty p orbital)

4) Reduction of nitro compounds (compounds with a N attached to an aromatic ring) (forms a singlet)

Which systems can nitrenes be added to

alkenes

aromatic systems (aromatic ring undergoes ring expansion in azepine synthesis)

what is the difference between triplet and singlet nitrene insertion into C-H bonds

singlet insertion involves a concerted process to form a product which retains the configuration (diagnostic of a singlet nitrene)

triplet insertion involves a radical reaction and forms a racemic product

what does the curtius rearrangement involve

converts an acyl chloride into a primary amine using an insertion into a C-C bond

N3 attacks the C=O of the acyl chloride, and kicks out the Cl to form an acyl azide

acyl azide can either undergo 1,1-elimination and proceed via nitrene (photochemical) or undergo a concerted process (thermal) to form an isocyanate

isocyanate undergoes decarboxylation to form a primary amine

What does the Hoffman rearrangement involve

abstracting CO2 from an amide to make an amine

remove an H from the N of the amide with OH-

Add a Br instead

Use OH- to take off the remaining H

next step can either be a concerted process or proceed via the nitrene intermediate

multi-step reaction to get an amine

What is Bredt's rule

Double bonds do not form to bridgehead carbons since too much strain is introduced into the system

If there is inversion in stereochemistry in a substitution what can we assume

substitution by an SN2 process

If there is retention in stereochemistry in a substitution what can we assume

neighbouring group participation (retention via a double inversion process)

What does the pinacol rearrangement involve

forms 1,2-diols but can then undergo subsequent rearrangement of these species to form substituted ketone products

What is the orbital overlap evidence for the pinacol rearrangement

adopt the chair conformation in the intermediate state

has to be antiperiplanar to the LG

What does the semi-pinacol rearrangement involve

After selective activation of one of the hydroxyl groups, several LGs are possible (halogens, tosylates, mesylates and phosphonates)

e.g. react a dihydroxy with TsCl and pyridine to make a molecule with an OTS LG

Look for the anti-periplanar relationship between the bond and the LG

Lone pair on remaining OH comes down to form a C=O

Bonding pair from bond anti-periplanar to the OTS attacks the Carbon attached to the LG, and eliminates the LG

*anything that can be activated to generate a carbocation can be used

What does the Tiffeneau-Demjanoc rearrangement involve

Activates primary amines to make diazonium salt LG

selective activation of the amine group by NO2

What does the benzil-benzilic rearrangement involve

activating a benzil molecule with OH-

1,2-shift of the phenyl group

Addition of H+ to the O- to form benzilic acid

What happens when a 1,2-diketone undergo a reaction in the presence of a strong base

forms alpha-hydroxycarboxylic acids

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What does the Favorskii rearrangement involve

a base induced rearrangement

commenly a ketone reacts via a reactive syclic propanone intermediate to form an ester product

abstract beta hydrogen from the ketone molecule with EtO- to form a double bond and a C-O (-)

C=O reforms, double bond breaks, LG is kicked out

forms a strained carbonyl ring system

EtO- attacks the carbonyl to form C-O(-)

C=O reforms to and ring breaks to form the most stable anion (can be stabilised through resonance)

React with EtOH to form an ester

In done in a cyclic system, there is ring contraction (ring gets smaller)

What does the Eschenmoser fragmentation involve

enables the transformation of an alpha,beta-epoxyketone to an alkyne and a carbonyl unit through the action of an aryl sulfonylhydrazines

involves the formation of an epoxide ring with NaOH and H2O2

epoxide ring forms a hydrazone

epoxide ring is broken open

end products = alkyne + carbonyl unit

What does the Prins reaction involve

nucleophilic attack of an alkene onto an activated carbonyl (normally an aldehyde)

if there is a hydroxy group on the alkene, the OH is a better nucleophile so attacks the carbonyl unit

activate the carbonyl through a proton source or a lewis acid

3 products can be generated:

Allylic system

1,3-diols

acetals

How is an allylic system formed in the prins reaction

through an intramolecular process

includes proton shuffling within the molecule

an SN1 type elimination

finally, the prins step which involves the alkene attack onto the activated carbonyl but they are part of the same structure

How is a 1,3-diol formed in the prins reaction

forms an oxonium species which undergoes the prins reaction

the attack of water from the least sterically hindered face

How is an acetal formed in the prins reaction

an FeCl3 catalyst is used

forms a mixture of diastereoisomers of acetal molecules

What does the Bayer-Villiger Rearrangement involve

uses a peroxide to convert a ketone to an ester (cyclic ketones are converted into lactones)

protonate the carboxyl group

react with a carboxylic acid

do some proton shuffling to set up an antiperiplanar relationship between the bond and LG

this migration step with the antiperiplanar relationship retains the stereochemistry

What is migratory aptitude

the group best able to support positive charge migrates for aromatic groups

The more electron donating, the more electron rich the carbon becomes, the better nucleophile it becomes

The more substituted side is more likely to migrate

tertiary alkyl > secondary > aryl > primary > methyl

What does the Criegee rearrangement involve

a tertiary alcohol is cleaved by oxidation of a peroxuacid to form a ketone

similar mechanism to Bayer-Villiger Rearrangement

What does the Beckmann rearrangement involve

the conversion of an oxime to a secondary amide

React an aldehyde with H2N-OH and H+ to get an oxime

react oxime with H2SO4 to establish bond migration-LG periplanar relationship

ring opening and add one more side to the ring e.g. 6 membered ring turns into a 7 membered ring

Add H2O to quench the positive charge to get a molecule which can undergo tautomerisation to produce a secondary amide

What does the Beckmann fragmentation involve

ring opening

react a hydroxy ketone with HONH2 to convert the C=O into C=N-OH

react with acyl chloride to set up antiperiplanar relationship

generate HCl, CO2, CO and the ring opened structure (entropy and enthalpy are favourable)

What does the Schmidt reaction involve

forms an amide

react ketone with NH4 to get a C=O=H bond

React with N3 to break C=O

Eliminate water through the attack of the N lp

activated complex with an antiperiplanar relationship

lose N2

Generate a ring with one more side than what you started with

Add water to quench positive charge

-H(+)

tautomerise to get an amide

What does the Neber rearrangement involve

convertes a ketoxime (oxime formed from a ketone) into an alpha-aminoketone

Beckmann rearrangement is a competing reaction

React a ketone with H2N-OH to get an enolisable compound

react with TsCl and Et3N to knock off the OH with TsO ( a good LG)

deprotonate alpha carbon with Et3N to form an anion

Get the electron on the negative charge to attack the N and kick out TsO, forming an azarine (cyclic)

Add H2O to break C=N, this forms a very strained ring

lp on oxygen forms C=O and breaks the C-N bond which is holding the ring together

ring is broken to form an alpha-aminoketone