Metal Mediated Synthesis

Question 1

Describe general cross-coupling catalysis reactions.

Answer 1

• nucleophilic substitution at an sp²-hybridised carbon by used a TM mediated catayst
• the classifications of the reactions are based on the main group metal used to transfer R’ in the transmetallation step
• originally suggested for NiP complex, but many Pd-catalysed reactions have been developed

Steps involved:

1. Oxidative addition
2. Transmetallation
3. Reductive elimination

Question 2

Give the general scheme for cross-coupling catalysis.

Answer 2

Question 3

Describe the oxidative addition step of cross-coupling catalysis.

Answer 3

The addition of RX to the active catalyst.

1. Oxidation of Pd(0) to Pd(II)
2. Increase in valence electron count at Pd - 14 in [L₂Pd] to 16 in [L₂Pd(R)(X)]
3. Increase in coordination number of Pd - 2 to 4
4. Introduces one half of the desired C-C coupled product (R)

The strength of the R-X bond will determine if this is the RDS of the cycle. C-X bond strengths decrease down group 17, so organochlorides are not favoured.

Question 4

Give two examples of oxidative addition to Pd.

Answer 4

Question 5

Describe the transmetallation step of cross-coupling catalysis.

Answer 5

It is the key RDS for cycles with weakly nucleophilic transmetallating agents (R’M). The second half of the desired product (R’) is coordinated to Pd and stable metal salts MX are eliminated.

Question 6

Show the mechanism for transmetallation in cross-coupling catalysis.

Answer 6

Question 7

Describe the reductive elimination step of cross-coupling catalysis.

Answer 7

The formation of a new C-C bond (and therefore the desired RR’ product).

• Reduction of Pd(II) to Pd(0)
• Lowering of the valence electron count at Pd - 16 to 14
• Coordination number of Pd reduced - 4 to 2

Question 8

Show the reaction scheme for reductive elimination is cross-coupling catalysis.

Answer 8

Question 9

Describe catalyst activation in cross-coupling catalysis.

Answer 9

We need Pd with a vacant site in the zero oxidation state. Stable starting materials such as Pd(OAc)₂ need to be reduced. There are many routes, with the most common involving organometallics.

The active catalyst in many C-C cross couplings is thought to be [L₂Pd], where L is typically a phosphine ligand and Pd is in the zero oxidation state.

Question 10

Give two ways of generating the active catalyst in cross-coupling catalysis.

Answer 10

Question 11

Describe the effect of the C-X bond on the cross-coupling reaction.

Answer 11

C-X with an element higher up the group, such as C-Cl, requires an electron rich L e.g. ^tBu₃P.

Weaker bonds, such as C-I, require less activating phosphine ligands due to the bond being easier to activate.

Question 12

Draw the general catalytic cycle of cross-coupling catalysis.

Answer 12

Question 13

Describe Pd catalyst speciation in cross-coupling catalysis.

Answer 13

Question 14

Give a general scheme for Kumada cross-coupling.

Answer 14

Question 15

How is the active catalst generated in Kumada cross coupling?

Answer 15

Question 16

What is the problem with Kumada cross coupling?

Answer 16

Functional group tolerance is low. Compounds with sensitive functional groups, e.g. ketones, esters, imines, are prone to nucleophilic attack by organometallics like Grignard reagents.

Question 17

What is an advantage of Kumada cross coupling?

Answer 17

It’s possible to use Fe, removing the reliance on precious Pd.

Question 18

Describe Negishi cross-coupling.

Answer 18

Negishi proposed that less electropositive metals e.g. Al/Zr, could act as transmetallating reagents in the Kumada-type coupling reactions.

Question 19

What modifications were applied to Negishi coupling?

Answer 19

The addition of ZnCl₂ was found to increase the reactivity of the transmetallating reagent. ZnCl₂ reacts with the original organometallic to produce an alkenylzinc species. This is thought to occur in situ and are thought to lead to a fast transmetallation step.

Question 20

Describe Stille cross-coupling.

Answer 20

The general scheme is:

R-X + R’-SnBu₃ –> R-R’ + X-SnBu₃ via Pd⁽⁰⁾

R, R’ and X directly affect the rates of OA and TM steps in the cycle.

Key features include:

1. Near complete functional group tolerance
2. Organostannanes, organotriflates and organohalides are air and moisture stable

Question 21

Draw a typical Stille cross-coupling reaction.

Answer 21

Question 22

What is the problem with Stille cross-coupling?

Answer 22

The Sn problem and the fluoride effect.

Question 23

Draw a general scheme for a typical Suzuki-Miyaura cross-coupling.

Answer 23

Question 24

What is the important mechanistic difference in Suzuki cross-coupling?

Answer 24

The formation of a ‘Pd-OH’ species.

Question 25

Describe the Br vs I chemoselectivity in cross-coupling catalysis.

Answer 25

The reaction usually forms a major product where I has been substituted. This can be demonstrated via a Negishi reaction with Br and I on opposite sides of an aromatic ring.

Question 26

Describe halogen regioselectivity in cross-coupling catalysis.

Answer 26

Question 27

Describe Br vs OTf chemoselectivity in cross-coupling reactions.

Answer 27

Question 28

Why is Br vs OTf chemoselectivity observed in Stille vs Suzuki cross-coupling reactions?

Answer 28

Question 29

Describe C-H activation processes.

Answer 29

Essentially replacing the organometallic in cross-coupling reactions with a C-H bond that is reactive towards functionalisation.

1. Sonogashira cross-coupling
2. The Heck reaction (variant of the Sonogashira reaction)

Question 30

Give the general scheme for Sonogashira cross-coupling.

Answer 30

Question 31

What is the role of the CuI in Sonogashira cross coupling?

Answer 31

It aids Pd activation and causes the acetylene H to become more acidic (therefore more reactive).

Question 32

Describe the Heck reaction.

Answer 32

Although it’s another example of C-H functionalisation, it does not proceed by the usual catalytic cycle. The appearance β-hydride elimination as an essential step sets this reaction apart.

RX must not contain an alkyl-aryl group, as β-hydride elimination directly after OA would lead to unwanted by-products.

Question 33

Describe atom efficiency in cross-coupling.

Answer 33

The cross-coupling reactions are quite complex and involve many steps. For example, the Suzuki coupling requires both reactants to be pre-functionalised. However, these reactions can be simplified by removing the need for reactant pre-functionalisation. The most atom efficient is the reaction where neither reactant is pre-activated.

Question 34

Give an example of double C-H bond activation.

Answer 34

Question 35

What are the different catalyst types in alkene metathesis?

Answer 35

1. Schrock catalyst
2. Grubbs 1st generation
3. Grubbs 2nd generation

Question 36

Give the mechanism for alkene metathesis.

Answer 36

It’s important to know how the Ru-carbene reacts with an alkene via a metalloruthenacycle intermediate.

Question 37

Show how the Schrock catalyst can be used in ring-closing metathesis.

Answer 37

Question 38

Show how the Grubbs 2nd generation catalyst can be used in ring-closing metathesis.

Answer 38

Question 39

Describe macrocyclisation via RCM.

Answer 39

• reactant concentration is critical for a successful RCM macrocyclisation reaction
• interactions that increase the rigidity of the substrate and reduce the entropic cost of the cyclisation can be beneficial in RCM
• remote substituents can influence reaction efficacy and alkene stereoselectivity

Question 40

Give an example of both a non-selective and a selective cross metathesis reactions.

Answer 40

Question 41

Explain non-selective vs selective cross metathesis reactions.

Answer 41

The difference in E/Z stereoisomer ratios reflects the enhanced activity of Grubbs 2nd gen. catalyst vis Grubbs 1st gen. catalyst. The 2nd gen. catalyst cat catalyse a secondary metathesis of the product (e.g. the Z-isomer), allowing equilibration of the alkene to the thermodynamically stable E-isomer.

• the steric bulk in one alkene can assist in favouring CM over homodimerisation
• the lower yield for the unprotected alcohol is because of homodimerisation

Question 42

Describe the Pauson-Khand reaction.

Answer 42

It’s a formal [2+2+1] cycloaddition reaction of an alkyne, an alkene and carbon monoxide. It is mediated by a range of different metals and can either be catalytic or stoichiometric.

Question 43

Give an example of an intramolecular and an intermolecular PK reaction.

Answer 43

Question 44

Give an example of a typical catalytic PK reaction.

Answer 44

Question 45

Give an example of a typical stoichiometric PK reaction.

Answer 45

Question 46

What are the limitations of the PK reaction?

Answer 46

• Co₂(CO)₈ is toxic and difficult to handle
• the catalytic reaction only works intramolecularly
• intermolecular reactions are much more difficult
  
  • side reactions can be a problem here

Question 47

Describe substituent effects in the intermolecular PK reaction.

Answer 47

• mono-substituted ‘terminal’ acetylenes will give PK products where the substituent is in the alpha-position of the enone
  
  • regiochemistry is dominated by steric effects
• for disubstituted acetylenes, an EDG tends to prefer the alpha-position while an EWG prefers the beta-position of the enone
  
  • regiochemistry is dominated by electronic effects (sterics still play a role)

Question 48

Give a reaction mechanism showing how a Davephos ligand aids C-H functionalisation.

Answer 48