Synthesis of organolithium reagents I

Question 1

How are organolithium compounds made and what does the reaction require?

Answer 1

• Organolithium compounds can be made by oxidative insertion of Li⁰ into a C-Hal bond. These reactions are slow and require heating
• They can also be made by halogen-lithium exchange, where a C-Hal bond exchanges with a C-Li. These reactions are fast and occur at low temps
• The driving force for Halogen-Lithium exchange is the formation of a more stable C-Li from a less stable C-Li compound

Question 2

Why is BuLi less stable than the product?
(This is what allows the reaction to occur)

Answer 2

• BuLi is a tertiary organiolithium which is on a sp³ hybridised carbon while the lithium on the product is on a sp² hybridised carbon
• The sp² hybridised orbital has more s character, so the electrons are held closer to the nucleus, so that the negative charge is stabilised by the electrostatic interaction with the positive nucleus

Question 3

What other factors affect the stability of the product C-Li?

Answer 3

• sp > sp² > sp³
• sp³ : 1° > 2° > 3°
• Conjugation increases stability (more atoms to delocalise the charge across)
• Internal heteroatoms co-ordination increases stability
• α-heteroatom stabilisation - heteroatom will withdraw some of the electron density from that carbon centre with the build up of negative charge

Question 4

How many equivalents of BuLi are necessary to form Al-Li from tBuLi and ArBr

Answer 4

• When using BuLi, we need 2 equivalents
• We use one equivalent to displace the electrophile
• The second equivalnet is used to eliminate H-Hal and prevent to decomposition of X-Li (this is because X-Li is basic and can reaction with H-Hal)
• However, this reaction requires excess tBuLi because we are destroying the X-Li needed for the reaction to occur

Question 5

Why is there a need for a silicon protecting group in this organolithium reaction?

Answer 5

• The silicon protecting group is instead of an alcohol group
• IF we had an unprotected alcohol, the organolithium reagent formed in the first step would be destroyed by picking a proton off the alcohol
• We need to avoid any source of protons when using organolithium chemistry

Question 6

What is transmetallation?

Answer 6

• Instead of halogen-lithium exchange (i.e. exchanging C-Hal + C-Li bonds)
• Organometallics can also be made by transmetallation (i.e. exchanging C-MgX or C-Li with a less electropositive metal., e.g. C-Cu, C-Sn etc)
• This gives us less reactive organometallics that are easier to control
• Like for Hal-Li exchange, the driving force for this reaction is the formation of a more stable C-Li from a less stable/more reactive C-Li

Question 7

The driving force for this reaction is the formation of a more stable C-Li from a less stable C-Li
How?

Answer 7

The higher the electronegativity difference between the carbon and the metal, the more ionic that bond is
Therefore, the more reactive our reagent

An organolithium reagent is more reactive than a organo-tin reagent
Hence can displace Tins bonds, forming a more stable product

Question 8

What are some advantages of tin compounds in organolithium chemistry

Answer 8

• Available via several routes (e.g. hydrostannylation
• Sn compounds are stable: can be easily purifed, stored, etc - can store as intermediates, the react with an organolithium when needed
• Sn to Li exchange is rapid and high yielding

Question 9

What are some disadvantages of using tin compounds in organolithium chemistry?

Answer 9

• Tin compounds are very toxic
• By-products can be difficult to remove
• Indirect route compared to other methods (often made from R-Br to R-Li to R-Sn)
• Copper can be a less toxic alternative

Question 10

We can also make organolithiums reagents by deprotonation of C-H bonds
What does this require?

Answer 10

• A strong base (BuLi or LDA) is necessary
• Directing groups (DG) enable regioselective ortho-lithiation (deprotonation of aromatic C-H bonds)
• Electrophile that we need to make the molecule we are trying to make (El)

Question 11

How does a directing group coordinate the lithium in our base

Answer 11

This draw the base close to this specific reactive centre and this specific proton
So we get very selective deprotonation on this site

Question 12

Here are some examples of directing groups for ortho-lithiation
What do they all have in common?

Answer 12

They all have hetroatoms that can coordinate to our electropositive lithium
Nitrogen has a high affinity to metals so is a good DG, oxygens and halogens, less so
(we cannot use functional groups that would react with BuLi: esters, ketones etc)

Question 13

You can have two directing groups in ortho-lithium which can reinforce: both groups direct to the same position
How does this work in the example below

Answer 13

Both DG draw the base to the specific reaction centre and proton
Hence we get a specific deprotonation at this site

Question 14

You can have two directing groups in ortho-lithium which can compete, where the stronger DG wins
How does this work in the example below

Answer 14

• Nitrogen is the stronger DG so the lithium is added one that site
• (In practice you may want to try to avoid using two different DG on the molecule because while the theory the stronger DG wins, you’ll always get a small mixture, due to a side reaction giving you the other product as well)