Diastereocontrol in Cyclic systems 1

Question 1

What is a challenge with stereocontrol involving a carbonyl group
e.g. ketone with a stereocentre +NaBH4

Answer 1

1. To achieve a stereoselective reaction at the carbonyl group, the existing stereocentre would have to influence the direction of attack of the nucleophile at the C=O group
2. Hard as 3 bond separation and carbon chain is highly flexible- able to access many different conformations - produced racemic mixture

Question 2

How can you increase the stereocontrol of a carbonyl molecule

Answer 2

1. Join the ends of the molecule into a ring
2. A cyclic molecule is much less flexible and has only one low energy conformation in a lot of cases e.g. T-bu is a conformational-biasing group as has 99% preference for equatorial

Question 3

How should you draw cyclohexanones

Answer 3

1. C=O group at pointy end of chiar bisecting the angle between axial and equatorial
2. Flat carbon as sp2 hybridised

Question 4

Which direction do small and large nucleophiles attack from

Answer 4

1. Small nucleophiles = axially
2. Large nucleophiles = equatorially

Question 5

Why do large nucleophiles attack equatorially

Answer 5

1. Large nucleophile attack suffers steric interactions with diaxial hydrogens during axial attack

Question 6

Why do small nucleophiles prefer axial attack on cyclohexanones

Answer 6

1. C=O bond in cyclohexanone is not exactly co-planar with the neighbouring C-H bonds- 4 degrees below
2. During axial attack, the onset of rehybridization form sp2 to sp3 pushes the C=O group downwards away from the neighbouring C-H
3. But opposite is true for equatorial attack as torsional strain increase in he TS as the molecule begins to pass through an unfavourable eclipsed conformation

Question 7

What does torsional steering mean

Answer 7

1. Describes reactions whose selectivity is governed by minimisation of developing torsional strain interactions in the TS

Question 8

What is torsional strain

Answer 8

1. Strain caused by the close approach of atoms or groups separated by three covalent bonds.
2. In the molecule W-X-Y-Z, atoms W and Z may experience torsional strain if a particular conformation (such as an eclipsed conformation) brings these atoms into close proximity.

Question 9

Do these carbon nucleophiles prefer axial or equatorial attack:
Li-Alkyne
Me-Li
Phenyl-Li
Me-MgBr
t-Bu-MgBr

Answer 9

1. Li-Alkyne = Axial - v small
2. Me-Li = 35% axial
3. Phenyl-Li = 42% axial - behaves smaller than you would think as flat
4. Me-MgBr = 41% axial
5. t-Bu-MgBr = 0% axial - v large

Question 10

What are the small = axial attack etc arguments relevant for

Answer 10

1. IRREVERSIBLE ADDITION
2. under kinetic control - to do with activation height of energy barrier

Question 11

When does is attack on a cyclohexanone provide the thermodynamic (most stable) product

Answer 11

1. reversible reaction
2. involving configurationally labile reactive intermediates (radicals)

Question 12

Describe electrophilic additions to cyclohexenes

Answer 12

1. Bromine and related electrophiles add to cyclohexenes in a trans-diaxial fashion
2. Goes through a favoured chair-like TS - Produces diaxial chair product
3. Diequatorial addition goes through twist-boat-like TS, then produces diaxial twist boat - which forms diequatorial chair- equilibrium

Question 13

Which of diaxial and diequatorial products in electrophilic addition to cyclohexenes is favoured

Answer 13

1. Both pathways are stereoelectronically-mandated to give trans-diaxial products
2. But through the chair-like transition state is faster as the TS is lower in energy

Question 14

Describe alkylations of cyclohexanone enolates

Answer 14

1. For cyclohexanone-derived enolates, axial attack of electrophile is stereoelectronically required
2. Only way that electrophiles can interact productively with the Pi-orbital
3. But selectivity for alkylation of cyclohexanones is much poorer than for bromination - 55% axial favoured compared to 96%

Question 15

Why is the selectivity for alkylation of cyclohexanones much poorer than for bromination

Answer 15

1. Poor selectivity in the enolate alkylation reflects the very early nature of the TS- Occurs much earlier on the reaction coordinate
2. Therefore the TS looks much more like the enolate than the products
3. The reaction does therefore not feel the developing strain with the twist-boat product so much
4. Therefore less differentiation between the competing TSs leading to lower selectivity

Question 16

Why does enolate alkylations have early TS

Answer 16

1. Mainly because the alkylation step is so exothermic
2. As we regenerate a very stable C=O bond from the less strong C=C bond in the enolate ion
3. We make a strong C-C bond at the expense of a much weaker C-I bond
4. In general exothermic = earlier transition states

Question 17

What is an alternative strategy for alkylation of cyclohexanone enolates to improve selectivity

Answer 17

1. Use enamines as nucleophiles
2. Much less reactive than lithium enolates- later TS

Question 17

What is an alternative strategy for alkylation of cyclohexanone enolates to improve selectivity

Answer 17

1. Use enamines as nucleophiles
2. Much less reactive than lithium enolates- later TS
3. Produces trans isomer

Question 18

What is a problem with using enamines as nucleophiles in the alkylation of cyclohexanone

Answer 18

1. Issue with competing N-alkylation when using simple alkyl halides which lowers the yield

Question 19

What are the steps in the alkylation of cyclohexanone enolates using enamines

Answer 19

1. Add pyrrolidine to produce an enamine
2. Add Alkylhalide to form iminium salt
3. Add H3O+ to produce the trans isomer
4. Then N-alkylated enamine is the major product though

Question 20

How can the cis-isomer product of a cyclohexanone be accessed

Answer 20

1. Rely on thermodynamic control via base-catalysed epimerisation
2. First LDA, THF then MEI
3. Produces not stereoselective trans isomer
4. Then add NaOMe, MeOH to produce cis isomer - reversible reaction

Question 21

What is another cyclic compound whihc is attacked axialy

Answer 21

1. Cyclic oxocarbenium ions
2. Formed in SN1 processes from cyclic acetals under acidic conditions
3. Attack on double bond to give a chair like TS

Question 22

What would reverse process of axial attack on cyclic oxocarbenium ions look like

Answer 22

1. Expulsion of a leaving group to give an oxocarbenium ion must also proceed from the axial isomer
2. Forward and reverse reactions share the same TS
3. Principle of microscopic reversibility

Question 23

Describe conjugate additions to cyclohexenones

Answer 23

1. The principle of axial attack can be extended to cyclohexenones which contain 3 contiguous sp2 centres- hence 5 co-planar ring atoms in a so-called envelope conformation

Question 24

How can you draw cyclohexenones in an exam to make it easier

Answer 24

1. Should draw envelope conformation but TS for nucleophilic attack are difficult to draw
2. Pretend that cyclohexenone adopts a half-chair conformation instead

Question 25

What does axial attack of nucleophile on cyclohexanone produce

Answer 25

1. Equatorial alcohol