Simon Lewis

Question 1

What is a natural product?

Answer 1

A substance/compound/molecule that has been made by a living thing

Question 2

What is an opioid/opiate?

Answer 2

Very potent painkillers

Risk of addiction

Question 3

What is a non natural product?

Answer 3

Does not exist in nature made by chemists

Question 4

What is retrosynthesis?

Answer 4

Known as the dissconnection approach

Process for devising a synthetic route to target a molecule by working backwards from that molecules

Question 5

Give a brief description of how retrosynthesis is done

Answer 5

A molecule is br open down into simpler fragments called precursors. These fragments are broken down into smaller fragments and this process is repaeated until we get fragments that are comercially available

Question 6

What is the name given to the fragments when a bond is broken?

Answer 6

Synth on

Question 7

What are synthons?

Answer 7

Hypothetical compounds that would react together is they existed

Question 8

How are Enolates normally generated?

Answer 8

By the deprotonation of the corresponding carbonyl

Question 9

What are the typical bases in enolate generation and why are they good?

Answer 9

Alkoxides (usually with Na as the counterion)
Alkali metal hydrides NaNH2, KNH2
Lithium diisopropylamide (LDA)
Lithium Hexamethyldisilazide (LHMDS)
These are good because they are soluble in inert solvents such as THF and are hindered and therefore non nucleophilic

Question 10

What is the pKa of ethoxide?

Answer 10

15

Question 11

What is the pKa of tert-butoxide?

Answer 11

17

Question 12

What is the pKa of LHMDS in THF?

Answer 12

26

Question 13

What is the pKa of LDA in THF?

Answer 13

36

Question 14

What is the pKa of sodium hydride?

Answer 14

36

Question 15

What is the pKa of sodium amide?

Answer 15

38

Question 16

Why are alkyllithiums not usually used for enolate formation?

Answer 16

They are good nucleiplhiles which can lead to side reactions.

Question 17

What is the pKa of phenyl lithium?

Answer 17

43

Question 18

What is the pKa of n-butyllithium?

Answer 18

48

Question 19

What is the pKa of sec-butyllithium?

Answer 19

51

Question 20

What is the pKa of tert-butyllithium?

Answer 20

53

Question 21

What is the pKa value for a tertiary amide?

Answer 21

30

Question 22

What is the pKa value for an ester?

Answer 22

24.5

Question 23

What is the pKa value for a ketone?

Answer 23

19-20

Question 24

What is the pKa value for an aldehyde?

Answer 24

17

Question 25

What is the pKa value for a malonate (a beta diester)?

Answer 25

13

Question 26

What is the pKa value for a beta ketoester

Answer 26

11

Question 27

What is the pKa value for a beta diketone?

Answer 27

9

Question 28

What is the rate of alkylation of enolates dependant on?

Answer 28

Solvent

Question 29

Give examples of good cation solvators and describe why they are good?

Answer 29

DMF, DMSO, HMPA | They leave a naked reactive anion

Question 30

Give examples of weakly polar solvents and descrbe why they can still be used for enolation?

Answer 30

THF and DME | Still able to coordinate cations but with a smaller charge separation generating less reactive enolates

Question 31

What type of alkylation does Li+ promote?

Answer 31

C alkylation as it binds tightly to oxygen

Question 32

What type of alkylation do larger cations promote?

Answer 32

O alkylation

Question 33

In regards to the regioselective deprotonation, what enolate is fasted formed and how is it formed?

Answer 33

The kinetic enolate | It is usually formed by the removal of the least hindered proton

Question 34

What are good conditions for forming the kinetic enolate?

Answer 34

Excess of a strong hindered base such as LDA at a low temperature -78 degrees

Question 35

What are good conditions for forming the thermodynamic enolate?

Answer 35

Adding a strong base to the ketone (often at room temperature or above) to form the more substituated enolate

Question 36

What is the ratio of kinetic to thermodynamic enolate formed in LDA at -78 degrees?

Answer 36

99:1

Question 37

What is the ratio of kinetic to thermodynamic enolate formed with KOtBu at room temperature?

Answer 37

22:78

Question 38

What is a useful way to trap enolates?

Answer 38

To prepare enolsilanes These are generated by trapping the enolate mixture with trimethylsilylchloride (TMS) The resultant enolsilanes can be separated by distillation Treatment with methyl lithium and an electrophileregenerates the enolate

Question 39

How do activating groups help to remove protons at desired positions?

Answer 39

Introduction of activating groups at a specific position increases the acidity of the desired proton. This is usually achieved by the introduction of a further EWG such as an ester After alkylation the activating group an be removed by hydrolysis and then decarboxylation

Question 40

What problems can occur with direct alkylation of ketones?

Answer 40

Double alkylation | Self condensation