Diastereocontrol in Acyclic systems 1

Question 1

Describe molecular orbitals for Pi-bond

Answer 1

1. P-orbital lobes within the antibonding pi* orbital are bent outwards
2. This has stereoelectronic implication for the chemistry of the C=O bond

Question 2

What are the stereoelectronic implications of the molecular orbital bending

Answer 2

1. The lowest conformation of acetaldehyde is one in which a C-H bond eclipses the C=O group as this gives the best orbital alignment for two stabilising sigmaC-H–>pi*-O interactions
2. This hyperconjugative interaction is also part of the reason that ketones are less reactive than aldehydes as there are more of these interactions to stabilise the C=O group

Question 3

What is the approach trajectory of nucleophiles to C=O bonds

Answer 3

1. Burgi-Duntz angle
2. 107+-2 Degrees

Question 4

Why is the Burgi-Duntz angle the approach trajectory

Answer 4

1. Maximises bonding
2. Minimises antibonding

Question 5

What is the conformation of an acetaldehyde undergoing nucleophilic attack

Answer 5

1. Not the same as its ground state lowest energy conformation
2. A staggered reactive conformation is adopted
3. Enables a sigma* C-H–>pi*C-O LUMO-lowering interaction which makes the C=O bond a better acceptor of electron density
4. Anti periplanar relationship between nuc and C-H bond lowers LUMO

Question 6

What model is used to explain addition of nucleophiles to alpha-chiral aldehydes/ketones

Answer 6

1. Felkin-Anh model

Question 7

What dictates the Felkin-Anh model

Answer 7

1. Alpha-substituents are electronically similar but differentiated by size
2. TSs are reactant like (early) rather than product-like (late)
3. Reaction occurs via the most reactive conformation of the carbonyl compound (sigma* orbital perpendicular to C=O bond)

Question 8

What are the rules of the FA model

Answer 8

1. The largest group is placed perpendicular to C=O to minimise steric interaction with incoming nucleophile- lowers LUMO
2. Nuc approaches at 107 degrees
3. Nucleophile approaches antiperiplanar to the C-L bond to give the best stereoelectronic interaction between the sigma-donor (sigmaNu-c) and sigma acceptor (sigma*C-L)
4. Nuc prefers attack alongside the smaller group S than the medium group M for steric reasons

Question 9

What happens when an electronegative heteroatom substituents on the alpha-stereocentre

Answer 9

1. For aldehydes/ketones with heteroatom (x) alpha-substituents (e.g. O,N,S,Hal) the most reactive conformation is one where the C-X bond is perpendicular to the C=O group
2. C-X bonds are generally better sigma-acceptors than C-H or C-C bonds (lower energy sigma*C-X orbitals) and offer greater hyperconjugative stabilisation in the transition state

Question 10

What elements have the best acceptor ability of sigma bonds

Answer 10

1. Acceptor ability of sigma bonds increases when going to the end of a period and down the group
2. Enhancement of the acceptor ability of sigma bonds within periods parallels the increase in electronegativity of X
3. whereas augmentation of acceptor ability in groups is opposite to the changes in electronegativity of X and is a consequence of lowering the energy of sigma*C-X orbitals

Question 11

What is the Cornforth-Evans model

Answer 11

1. Alternative to FA model based on dipole-dipole interactions
2. says most reactive conformation is one in which the C=O group and polar C-X bond are opposed in order to minimise dipole-dipole repulsion
3. In simple cases will lead to same prediction as polar F-A model

Question 12

What is the cram chelate model

Answer 12

1. Chelation effects can overturn the polar FA model
2. Cram chelate model used when aldehydes/ketones bear an alpha-heteroatom substituent capable of chelation to a metal ion
3. Predicts the opposite diastereomer to the polar F-A model
4. R group is antiperiplanar to Nu

Question 13

What are common alpha-heteroatom substituent groups that result in chelation

Answer 13

1. Almost always -OR groups
2. But can occur with other lewis basic moieties (OH,SR,NR2)
3. OSiR3 tend to chelate very poorly or not at all
4. Mg2+, Zn2+, Cu2+, Al3+, Ce3+ Ti4+ are all excellent chelators and Li+ as have high charge densities
5. Na+ and K+ are poor chelators as low charge density

Question 14

Are syn and anti descriptors product or mechanism dependent

Answer 14

1. Soft descriptors
2. Depend on how the chemist chooses to define the main carbon chain
3. Product not mechanism dependent `

Question 15

What does the partitioning between Cram chelate and polar FA pathways depend on

Answer 15

1. dependent on the O-protecting groups
2. Also dependent on the solvent and strongly Lewis basic solvents can suppress chelation by competing for the lewis acidic metal

Question 16

What is examples of solvents which are strongly chelating

Answer 16

1. THF- strongly coordinating to metals so less chelating for molecule
2. Et2O is not

Question 17

Describe the Frater-seebach alkylation of beta-hydroxyl carbonyl compounds

Answer 17

1. Involves diastereoselective alkylation of chelated dianion
2. steric effects override torsional effects
3. Reaction occurs on the opposite face to the Me group - even though TS has small amount of twist-boat character

Question 18

Describe 1,3 induction in C=O additions

Answer 18

1. A stereogenic centre at the beta-position can also strongly influence diastereoselectivity in c=o additions
2. But only when the stereocentre bears an electronegative substituent -OH or OR
3. Two general models to describe diastereoselectivity, both predict same diastereomer

Question 19

What are the models to describe diastereoselectivity for addition to beta position

Answer 19

1. Chelation control - half-chair conformation, avoid twist-boat TS
2. Dipole control- zig-zag conformation of the main chain, dipole minimisation - but difficult so focus on chelation control

Question 20

What dictates what model applies for diastereoselectivity for addition to beta position

Answer 20

1. Nature of lewis acid and identity of O-protecting group dictate if chelation is possible
2. BF3 is monodentate and incapable of chelation - dipole model more suitable
3. Steric effects only play a minor role in 1,3 induction

Question 21

What product is produced when an aldehyde reacts with organometallic nucleophile and with ketone and hydride nucleophile

Answer 21

1. 1,3-anti product
2. 1,3-syn product

Question 22

Describe 1,3 reduction in beta ketone- in narasaka-prasad reduction

Answer 22

1. diastereoselective reduction of beta-hydroxy ketones to syn-1,3-diols
2. Add Et2BOMe, NaBH4 to beta hydroxy ketone
3. Thought to occur via a chelate formed upon exchange of the methoxy substituent on boron by the substrate alcohol
4. Followed by intermolecular delivery of hydride from NaBH4
5. Formation of chairlike TS

Question 23

What often combines with reduction of 1,3-beta hydroxy ketones to syn-1,3-diols

Answer 23

1. Combination with the aldol reaction
2. Provide access to 1,3-diol

Question 24

How can the 1,3-anti product of beta-hydroxy ketone reduction be produced

Answer 24

1. Evans-saksena reduction
2. Uses Me4N+BH(OAc)3- as the reducing agent
3. Substrate directed reaction

Question 25

What is another method to produce the 1,3-anti product of beta-hydroxy ketone reduction be produced

Answer 25

1. SmI2 as a Lewis acid catalyst
2. Aldehyde as reducing agent
3. Can differentiate between the two resulting hydroxyl groups- one of them is selectively protected by the aldehyde in the process