Radicals in Synthesis

Question 1

What is a radical?

Answer 1

Atoms or molecules possessing a single electron in a reactive orbital. This makes most radicals very reactive.

Question 2

How can radicals be detected and observed?

Answer 2

Via EPR, a very sensitive technique for detecting radicals at low concentrations. Radicals with lifetimes considerably less than 1s can be deteced. It provides information on the nature and structure of the unpaired electron.

Question 3

Describe radical stability.

Answer 3

It’s related to the rate of radical formation and disappearance.

Question 4

Describe thermodynamic stability of a radical.

Answer 4

The bond dissociation energy (BDE) e.g. of R-H depends on the themodynamic stability of R•.

A lower BDE/weaker R-H bond means that the carbon centred radical is more stable. Carbon radical stability decreases in the order:

tertiary > seconday > primary > methyl

Question 5

What are the contributing factors to thermodynamic stability of a radical?

Answer 5

1. Induction - more +I groups means more stable a radical, because the carbon is 1 e^- deficient (7 instead of 8)
2. Hyperconjugation - the interaction of the p-orbital of the radical with a pair of bonding electrons in a neighbouring sigma bond. Electrons in the sigma bond are donated to the p-orbital of the radical.
3. Resonance - interaction of the p-orbital on a radical with a pi-bond or lone pair (3-electron bonding).
4. Hybridisation - increasing p-character of the orbital increases radical stabilisation. Homolysis of double bond C-H leaves the unpaired electron with a lot of s-character and lying at a right angle to the p-orbitals (e.g. C-H on benzene). This is not stabilised by delocalisation.

sp³ > sp² > sp (stability)

Question 6

Describe the lifetime of a radical.

Answer 6

Usually determined by steric factors. The larger the substituents attached to the radical centre, the more stable the radical and the longer the lifetime.

Usually reported as half-lives (t_1/2), aka the time taken for the concentration of radicals to fall to half the initial value.

Question 7

What are the different kinds of chain reactions?

Answer 7

1. Initiation - formation of radicals.
2. Propagation - formation of a different radical.
3. Termination - destruction of radicals.

Question 8

Describe initiation via thermolysis. Show how this occurs for peroxides and azo compounds.

Answer 8

Compounds with relatively weak covalent bonds undergo homolysis below 150ºC.

Question 9

Describe initiation via photolysis. Show how it occurs for halogens, organometallics and carbonyls.

Answer 9

Works if the compound absorbs light of an appropriate wavelength and the excited state undergoes dissociation/fragmentation. The energy of the photon must be enough to rupture a bond.

The mechanism for peroxides is the same as for thermolysis.

Question 10

Describe initiation via radiolysis. Show how it works for H₂O.

Answer 10

Uses high energy x-rays or gamma-radiation.

Question 11

Give the general process for initiation via oxidation.

Answer 11

Question 12

Show how initiation via oxidation occurs for carboxylic acids and carbonyls.

Answer 12

Question 13

Give the general process for initiation via reduction.

Answer 13

Question 14

Show how initiation via reduction occurs for peroxides, halides, carbonyls and diazonium salts.

Answer 14

Question 15

Give a general scheme demonstrating intermolecular radical abstraction.

Answer 15

Question 16

Give a general scheme demonstrating intramolecular radical abstraction.

Answer 16

Question 17

Give a general scheme demonstrating intermolecular radical addition to alkenes and alkynes.

Answer 17

Question 18

Give a general scheme demonstrating intramolecular radical addition to make rings and to aromatic rings.

Answer 18

Question 19

Give a general scheme demonstrating radical fragmentation.

Answer 19

Question 20

Describe the different termination reactions.

Answer 20

1. Recombination or coupling - the reverse of bond homolysis, the joining of two radicals (dimerisation).
2. Disproportionation - transfer of hydrogen atoms.
3. Electron transfer - oxidation (removal of an electron from a radical to form a cation) and reduction (addition of an electron to form an anion).

Question 21

Describe how enthalpy affects radical reactivity.

Answer 21

We can predict if a reaction will take place by considering the energies of the bonds broken and formed. Exothermic reactions result in strong bond formation and occur rapidly. Endothermic reactions resulting in products with weaker bonds are slow.

Enthalpy change = total energy of bonds broken - total energy of bonds formed

Question 22

Describe how entropy affects radical reactivity.

Answer 22

Reactions resulting in an increase in entropy by increasing the number of molecular species from reactants to products are favoured.

Question 23

Describe how steric effects affect radical reactivity.

Answer 23

Reactions with sterically hindered radicals require very strained TS’s with high enthalpy of activation and are disfavoured.

Steric effects explain the regioselective addition of radicals to alkenes (add to least hindered end) and sometimes the stereoselective formation of adducts.

Question 24

Describe how stereoelectronic effects affect radical reactivity.

Answer 24

For a radical to react, the single occupied orbital must overlap with either another of its own orbitals (intramolecular) or another molecule orbital (intermolecular).

In S_H2, a radical and a non-radical can orientate themselves to give a linear TS.

Question 25

Describe how polarity affects radical stability.

Answer 25

For reactions to occur, the interacting or frontier MOs must overlap efficiently and have similar energies. The frontier MO for a radical = SOMO.

• radicals adjacent to EDGs have a high energy SOMO and are nucleophilic radicals - likely to donate an electron to form a cation
• radicals adjacent to EWGs have a low energy SOMO and are electrophilic radicals - likely to accept an electron to form a anion

Question 26

Describe the orbitals in a reaction between a radical and a non-radical.

Answer 26

We need to consider the SOMO-HOMO and SOMO-LUMO interactions.

• electrophilic radicals (low energy SOMO) are closer in energy to the HOMO, so SOMO-HOMO dominates
• nucleophilic radicals (high energy SOMO) are closer in energy to the LUMO, so SOMO-LUMO dominates
• for addition to C=C bonds, nucleophilic radicals prefer to add to those with EWGs while electrophilic radicals prefer those with EDGs

Question 27

Describe how redox potential affects radical reactivity.

Answer 27

The rate of oxidation or reduction of radicals is determined by the redox potential of the redoc agent and the radical.

Nucleophilic radicals (with EDGs) are more easily oxidised to form cations. Electrophilic radicals are more easily reduced to form anions.

Question 28

What are the advanatages of using radicals in synthesis?

Answer 28

• neutral reaction conditions
• solvation less important than in ionic reactions
• synthesis of polar and sterically hindered compounds is possible

Question 29

What is the initiation reaction in the synthesis of hirsutene?

Answer 29

Fragmentation of AIBN.

Question 30

Give the propagation steps in the synthesis of hirsutene.

Answer 30

Question 31

What are the undesirable competing reactions in the synthesis of hirsutene?

Answer 31

• early reaction of A/B with Bu₃SnH - ‘simple reduction’
• reaction of A, B or C with another molecule of A, B or C
• reaction of A, B or C with Bu₃Sn•

Question 32

Give the pros and cons of Bu₃SnH.

Answer 32

Pros:

• extremely mild and selective
• easily handled and used
• most kinetically understood method
• radical lifetime is changed by varying [Bu₃SnH]

Cons:

• two functional groups are destroyed
• expensive and toxic
• removal on tin byproducts is often difficult

Question 33

What is a cleaner alternative to Bu₃SnH?

Answer 33

TTMSS.

• less toxic than Bu₃​SnH
• larger and can influence stereoselectivities of reactions
• more expensive than Bu₃SnH

Question 34

Describe Baldwin’s rules.

Answer 34

A series of general guidelines for predicting the relative favourability of cyclisation reactions to form 3- to 7-membered rings. Favoured cyclisations are those in which the length and nature of the linking chain enable the orbitals of the terminal atoms to achieve proper geometries for orbital overlp and reaction.

Geometry is either tet (sp³), trig (sp²) or dig (sp).

Question 35

Describe intermolecular reactions.

Answer 35

Can be less efficient than related intramolecular reactions. In Bu₃​SnH-mediated reactions, the first formed carbon radical has a choice of reaction pathways.

Question 36

Show how xanthates are formed.

Answer 36

Question 37

Show how xanthates react with Bu₃​SnH.

Answer 37

Question 38

Show how 1,5-hydrogen atom transfers can occur using Bu₃​SnH.

Answer 38

Question 39

Show how 1,5-hydrogen atom transfer can occur in carbonyls via photolysis.

Answer 39

Question 40

Show how 1,5-atom transfer can occur in nitrites via photolysis.

Answer 40

Question 41

What are radical-polar crossover reactions?

Answer 41

Reactions involving radical and ionic reactions in the same pot.

Question 42

Show how a radical-polar crossover reaction with arenediazonium salts, an alkene and Cu(I) catalyst can occur via radical oxidation.

Answer 42

Question 43

Show how a radical-polar crossover reaction can occur with haloalkenes, SmI₂ and an electrophile via radical reduction.

Answer 43