Metal-Mediated Synthesis

Question 1

Describe how to prepare a Grignard and an organolithium reagent and describe the range of reactivities of the different types of BuLi.

Answer 1

n-BuLi < s-BuLi < t-BuLi (v. pyrophoric)

Question 2

Show generally how to prepare zinc, tin and copper organometallics

Answer 2

Question 3

What is the reaction of a terminal alkyne with EtMgBr?

Answer 3

Ethane gas forms along with the alkyne-MgBr, which can then react as a nucleophile.

Question 4

Describe how different types organometallics react with a carbonyl-alkene system.

Answer 4

Hard nucleophiles attack the carbonyl position such as a grignard and form the alcohol although some of the 1,4 product will also form.

Cuprate, a softer nucleophile, will attack the alkene to form a 1,4 nucleophile.

Question 5

Generally describe cross-coupling reactions. When are catalysts required and what groups are best?

Answer 5

Generally: R-X + R’-M → R-R’ + MX

When R is alkyl, allyl (sp^{<span>3</span>} with alkene), benzyl (sp³ with benzene) no catalyst is needed.

For sp² centres such as aromatics, vinyls - catalysts are needed.

X is a halogen or halogen like and their reactivity depends on bond strength. Cl > Br (approx > OTf, OTs) > I.

Question 6

For carbon cross-coupling reactions at sp² centres, give the metal reagents for each type of coupling (Suzuki-Miyaura, Kumada, Negishi and Stille).

Answer 6

Ph-B(OH)₂ - Suzuki-Miyaura

Ph-MgX - Kumada

Ph-ZnX - Negishi

Ph-Sn(ⁿBu)₃ - Stille

Question 7

Show the oxidative addition of bonds to Pd⁽⁰⁾ in complexes and on nanoparticles.

Answer 7

Question 8

Draw and describe the transmetallation step of catalysis for Pd(II).

Answer 8

This the rate determining step for many catalytic cycles and has the driving force of elimination of MX salt.

Question 9

Draw the reductive elimination of carbon ligands from a Pd catalyst. How can the resultant Pd species be stabilised?

Answer 9

Question 10

Show the two ways to form the active Pd(0) species from trans-PdCl₂(PPh₃)₂ and describe the typical amounts of each part used (reduction via base and organometallic).

Answer 10

Question 11

What are the six factors that determine the kinetics of a catalytic cycle?

Answer 11

1. Bond strengths
2. Nucleophilicity of oragnometallic reagents (RX and R’M)
3. Lattice energy of MX
4. Rate of cis-trans isomerism
5. Nature of ligands
6. Rate of side reactions (e.g beta-hydride elimination)

Question 12

When might PPh₃ not be a suitable ligand for bond activation (O.A) and what can be used instead?

Answer 12

For Ph-Cl, PPh₃ will not activate the bond as it is not electron rich enough. Replacing the phosphine with P^tBu₃ is more electron donating and occupies the space of two ligands.

Ph-I has a weaker bond so it can be activated by less electron rich bonds such as PPh₃.

Question 13

Draw a generallised catalytic cycle for Pd carbon cross coupling including showing the precatalyst.

How do the rates of each step affect the efficiency and what is typically the RDS?

Answer 13

The closer the rates are together, the more efficient the catalysis. If one rate is slower, the catalytic intermediate before it may degrade and stop the cycle.

Transmetallation is typically the RDS for most halogens but for chlorine, it is typically oxidative addition.

Question 14

Describe how the form of the active Pd catalyst may change in a catalytic reaction. How does this affect the reactivity?

Answer 14

The Pd atoms may form a nanoparticle which is another form of the active catalyst. This is a quasi heterogeneous system. However the nanoparticles will precipitate out, stopping the catalytic activity.

This can be prevented by using polar, aprotic solvents to stabilise the catalysts.

Question 15

How can Pd contamination be prevented? Why is this important?

Answer 15

Particles of Pd contaminate drugs and other products made with Pd catalysts as many groups such as alkenes, nitrogen and oxygen atoms bind to Pd atoms.

This can be prevented with long chain thiol stabilisers to bind nanoparticles and EDTA to chelate atoms.

Question 16

Generally describe Kumada cross-coupling, including the solvent and catalysts used.

What are the tolerances? What alternative catalysts can be used?

Answer 16

Kumada cross coupling describes the reaction of Grignard with a halide. The catalyst is typically Pd(II) or Ni(II) which is reduced in situ. The solvent must be DRY THF (<50 ppm water).

As Grignards are used there is little functional group tolerancy. They will react with any electrophilic centre and protic positions will inhibit the action of Grignards.

Fe can be used instead of Pd (expensive and precious) but it isn’t as good.

Question 17

Generally describe Negishi coupling including reagents and their reactivities, tolerances and the reaction products.

How can the reaction be modified?

Answer 17

Negishi cross coupling uses a Zirconium reagent instead of a traditionally used Mg or Li reagent. This increases the TM step.

The reaction is tolerant to ester groups and uses a Pd catalyst. Ni can be used but the product is less stereoselective.

ZnCl₂ can be added to the reaction to increase the reactivity while retaining the selectivity. It is thought that the Zn replaces the Zr on the carbon in situ.

Question 18

Generally describe Stille cross-coupling, the tolerances, catalyst and any issues with the reaction.

Answer 18

Stille cros-coupling uses Sn with three n-Bu groups along with the added R group. It is extremely tolerant to functional groups and even air and moisture. The catalyst is a Pd(0) species.

The Sn byproducts (X-Sn(ⁿBu)₃) however are highly toxic. They are neutrilised with KF and K₂CO₃ with silica gel to replace the halide with F, making the group highly insoluble.

Question 19

Generally describe Suzuki-Miyaura cross-coupling giving specific conditions, catalyst and showing how the catalyst reacts differently to similar systems.

Answer 19

The metal used in Suzuki-Miyaura couplings use a R-B(OH)₂ species. The reaction relies on [^-OH] ions so a mild base of Na₂CO₃ is used with a THF/H₂O solvent system (typically 1:1).

Importantly, the Pd-OH species forms which is unlike other reactions with a Pd catalyst.

Question 20

When a catalyst activates a molecule with two possible locations, what is the preference of chemoselectivity?

Answer 20

The weakest bond is preferred to activate. This is because oxidative addition is irreversible so only the E_{<span>A</span>} matters.

Bond strengths: Cl > Br (> OTf/OTs) > I

Question 21

For a pyridine ring with Br atoms at 2 and 4, where will a Suzuki-Miyaura reaction occur? Why?

Answer 21

The preference will be to activate the Br at position 2 due to the electronegativity of the nitrogen pulling electron density from the C-Br bond and weakening it.

Question 22

For a benzene ring with Br and OTf groups, how and why do Stille (PdCl₂(dppp)) and Suzuki-Miyaura (Pd(PPh₃)₄) react at different sites?

Answer 22

The Stille catalyst has a bidentate ligand and therefore can dissociate the ^-OTf ligand which is better stablised than Br^-. OTf > Br

The Suzuki-Miyaura reaction requires going through the catalyst state with an OH ligand which is easier with the Br ligand. Br > OTf

Question 23

Describe Sonogashira cross-coupling and how the reaction proceeds. What are the strengths of this type of reaction?

Answer 23

The catalytic amount of Cu(I)I and Pd seperate this from other cross-couplings, known as a C-H activation.

This shows excellent functional group tolerance and not requiring difficult synthesis of organometallics.

Question 24

Describe a Heck reaction, giving the key functional group product. What key mechanism step occurs in the reaction which limits the reagents?

Answer 24

A Heck reaction is a Pd(0) (such as Pd(PPh₃)₄) catalysted reaction between an aryl/vinyl halogen (Cl-Ph, TfO-vinyl) and an alkene group. A base such as NaOAc is required.

The aryl/vinyl group must not have an alkyl group (e.g CH₃Ph) as beta-hydride elimination will occur.

Question 25

Describe how atom effeciency can affect reaction choice in cross-coupling. Describe reactions that have a very low and high atom efficiency.

Answer 25

Some reactions, such as Suzuki-Miyaura coupling, require both reagents to have modified groups, giving long preperation times.

The ideal scenario is where neither reagent needs changed groups, where H₂ is lost as a result of forming a new carbon bond. This requires complex systems such as diheterocyclic compounds to allow the hydrogens to be functionlised in alternate ways. Catalysts can give specificty in these reactions.

Question 26

Give the reagents, products and conditions of a Fagnou oxidative arylation.

Answer 26

Aryl group and alkyl group (normally heterocyclic ring), both with hydrogen bonds availible to be coupled. Pd(II) catalyst with mild base (CsOAc) and oxidant (either Cu(II) or Ag(I) depending on position linking).

Question 27

If you were linking two phenyl rings, which coupling reaction would be appropriate? Give complications for each.

Answer 27

1. Suzuki-Miyaura is best but requires lots of prep.
2. Kumada is cheaper but has low functional group tolerance.
3. Stille has high prep requirements and generates highly toxic waste.
4. C-H bond functionilisation is diffcult and selectivity may be low.

Question 28

Briefly describe the three main catalyst types for alkene metathesis. Which is the most popular?

Draw the key step in alkene metathesis with a generic Ru catalyst.

Answer 28

1. Schrock - Mo catalyst
2. Grubbs 1st gen - Ru with phosphine ligands
3. Grubbs 2nd gen - Ru with a NHC ligand

Grubbs 2 is the most popular.

Question 29

Describe the requirements for a successful ring-closing metathesis reaction with reference to the Thorpe-Ingold effect, reagent concetration and reagent structure.

Answer 29

RCM can be catalysed well by Schrock or Grubbs catalysts.

The Thorpe-Ingold effect is that having alkyl branching groups on the backbone of the reagent will increase cyclisation conversion and reduce polymerisation.

Reagent concentration needs to be very low, 0.001 M (100x less that normal).

OH or OR groups can coodinate to catalysts and must be protected. Reducing entropic cost of cyclisation is also beneficial.

Question 30

What is the main challenge in alkene cross metathesis and how can it be addressed? How do Grubbs catalysts compare in stereoselectivity?

Answer 30

The main challange is stopping homodimerisation. Reagents can be chosen which do not have this problem (symmetric alkenes) or steric bulk can be added to one reagent to favour cross-metathesis.

Both Grubbs catalysts mostly form the E isomer initially however G-I can set up and equlibrium between the isomers. Therefore G-II has a higher E yield.

Using bulky alkenes and G-II can lead to very high yield and stereoselective products.

Question 31

Generally describe the Pauson-Khand reaction, giving the reagents, product and catalyst.

Answer 31

The Pauson-Khand reaction is a [2+2+1] cycloaddition of an alkene, alkyne and CO. The reaction forms a 5 membered ring with an alpha-beta unstaturated ketone.

The catalyst is colbalt(0), Rh or Pd.

The alkene and alkyne are normally linked, and can have R groups which affects the regiochemistry.

Question 32

Generally describe the three catalyst stages of the Pauson-Khand reaction.

What are the limitations of the PK reaction and what dictates where the side groups of an alkyne will end up?

Answer 32

1. Alkyne binds to Co, replacing two CO ligands
2. Alkene binds to Co, replacing one CO ligand
3. Multiple steps occur replacing Co with CO.

Limitations are Co₂(CO)₈ toxicity and that intermolecular reactions are very difficult to perform.

A monosubstituted alkyne will place the R group at the alpha postion (next to CO), a di-substituted alkyne will place electron-donating groups at alpha and electron-withdrawing at beta. This is more signficant than steric effects.

Question 33

Briefly describe the Nazarov cyclisation of prepare a cyclopentenone ring.

Answer 33

A ketone with two beta alkenes will link with a strong acid to form a 5-membered ring. Limitations are in the use of strong acids.

Question 34

How can DMSO or NMO speed up a Pauson-Khand reaction?

Answer 34

DMSO and NMO both create a vacant site on the catalyst by reacting the with the carbonyl ligands and releasing them as CO₂.

Question 35

Describe the simple pros and cons of cross coupling and metathesis when decide which methods to use.

Answer 35

The most atomically economic transformation is often the best to use, it can be very hard to remove added reagents.

Cross coupling is reliable but requires substrate activation and requires lots of prep. C-H bond activation is better but often needs many catalytic reagents and scope is not well determined.

Cross metathesis is more economical and usually has mild conditions but often requires high catalysts loadings and aggregation can be problematic.