Clarke

Question 1

what features do you want in a protecting group

Answer 1

stability, improving stereo-selectivity and purification, orthogonal protection

Question 2

list some silicon protecting groups in order of stability

Answer 2

Me3Si (TMS) < Ph3Si < MetBuSi (TBS) < iPr3Si (TIPS) < Ph2tBuSi (TBDPS)

Question 3

What group is usually attached to a Si protecting group to act as a good leaving group for a reaction to happen?

Answer 3

Cl (or OTf)

Question 4

What two solvents are regularly used with silicon protecting groups

Answer 4

Triethylamine and imidazole

Question 5

What does a silicon group protect?

Answer 5

OH

Question 6

How do you remove a silicon protecting group?

Answer 6

F- ions. So HF is good for most «< but TBAF removes any

Question 7

What is orthogonal protection?

Answer 7

When two different protecting groups (of different strengths and removed by different molecules) are used in one molecule to preferentially react to one or the other OH -

Question 8

Name some other OH protecting groups

Answer 8

benzyl // MOM // MTM // MEM

Question 9

what’s the relationship between MOM, MTM and MEM?

Answer 9

MOM is methoxymethyl ether, MTM is methyl thiomethyl ether - so the same as MOM but with a sulfur, MEM is methoxyethoxymethyl ether - same as MOM but with an extra O bridged with ethyl.

Question 10

What is the main aim of an amine protecting group?

Answer 10

need to prevent basic/nucleophilic properties affecting other reagents

Question 11

Name some amine protecting groups

Answer 11

benzyl (Bn) // Tert-butylcarbonyl (BOC) // carboxybenzyl (Cbz) // fluorenylmethyloxycarbonyl (Fmoc)

(phthalimide, tosyl and tert-butyl as well).

Question 12

What would you deprotect an amine group with?

Answer 12

varies with different groups

Question 13

What amine protecting groups would you deprotect with Pd/C and H2?

Answer 13

Bn and Cbz

Question 14

What amine protecting groups would you deprotect with HCl or TFA?

Answer 14

BOC (TFA = trifluoroaceticacid)

Question 15

What amine protecting groups would you deprotect with NR3?

Answer 15

Fmoc

Question 16

What reagent do you use to add a protecting group to an amine?

Answer 16

Et3N

Question 17

What molecules can you use to ortholithiate a benzene ring?

Answer 17

oxazoline and bulky amide

Question 18

How does an oxazoline bond to a benzene with CO2H? + SOCl3

Answer 18

SOCl3 turns CO2H into COCl which is then attached by the nitrogen and another SOCl3 is used to cyclise the structure.

Question 19

Why do you need a bulky amide to ortholithiate a benzene ring? cf a dimethyl amino

Answer 19

a dimethyl amino would just results in an addition elimination reaction

Question 20

which is better at directing ortholithiation?
CONHR2 vs Oxazoline?
diether vs SO2R
OR vs C(=NR)R

Answer 20

CONHR2
SOR2
C(=NR)R

Question 21

How would you remove an oxazoline group?

Answer 21

hydrolyse with any acid

Question 22

What properties do multiple directing groups have on a benzene ring

Answer 22

they work together

Question 23

What ethers are good directing groups?

Answer 23

MOM and MEM

Question 24

how would you make an aniline a better ortholithiator?

Answer 24

convert to n-BOC aniline

Question 25

What reagents would you do a halogen-lithium exchange with?

Answer 25

nBuLi in Et2O or pentane | or 2:1 tBuLi

Question 26

What is a superbase? | What special property does it have regarding directing groups?

Answer 26

tBuOK - strong ligand for Li. | they have little influence - the most acidic proton will be removed.

Question 27

Name some reactions to make organometallic nucleophiles

Answer 27

transmetallation // grignard-exchange reaction // insertion/oxidative addition

Question 28

Which organometallic metals have problems with reactivity?

Answer 28

Mg and Zn - particle size too large and oxide layers present

Question 29

What are some methods of activating unreactive metals for organometallic reagents?

Answer 29

Stir under argon, iodine catalyse, dibromoethane catalyst, Reike (lithium in Napthalene)

Question 30

benefit of orangozinc?

Answer 30

more tolerant than organolithium and Mg and has good functional group tolerance

Question 31

What is the reformatsky reagent?

Answer 31

Br-ester + Zn ---> ester-CH2ZnBr

Question 32

What does the reformatsky reagent do?

Answer 32

ROOCBr --> reagent + ketone --> ROOCCH2[tertalcohol].

Question 33

How would a lewis base increase Zn reactivity?

Answer 33

organozinc donates electron density and breaks up aggregates

Question 34

How would a lewis acid increase Zn reactivity?

Answer 34

eg using MgCl2 - electrons can be removed from a C=O bond to make it more reactive to ZnBr reagent

Question 35

Name some reactions of organocuprates

Answer 35

Sn2 alkylations // Sn2' with allylic halides // limiting addition elimination // conjugate addition

Question 36

Where does Cu react in a conjugate addition reaction?

Answer 36

1,4

Question 37

Where are copper reagents normal made?

Answer 37

in situ

Question 38

Explain what you would do if you were using the Felkin-Anh model

Answer 38

put the large R group perpendicular to the C=O and then attack at the hydrogen which 'should' be around 107 degrees. Then rotate to put the large R group app to the nucleophile.

Question 39

Explain what you would do if you were using the chelation control model?

Answer 39

'think of the chelated intermediate' so put whatever would chelate with in line with the C=O then redraw staggered and nucleophilic attack where the H is 90 degrees to the C=O.

Question 40

Why would you use the chelation control model instead of the felkin-anh?

Answer 40

if there is a relatively unhindered heteroatom present that can form a 5/6 membered ring with the C=O and the metal ion. Or if chelation is unlikely but heteroatoms are present - the most stable configuration is the heteroatom 90 degrees to the C=O

Question 41

What is the optimal angle called for attacking the C=O

Answer 41

Burgi-Dunitz

Question 42

what are the 3 reactions in a Pd-cross-coupling catalytic cycle?

Answer 42

oxidative addition, transmetallation, reductive elimination

Question 43

Order aryl halides for reactivity

Answer 43

Ar-I > Ar-Br ~ Ar-OTf > Ar-Cl >>> Ar-F

Question 44

Order steric effects of subsitutents for reactivity

Answer 44

p-EWG > m-EWG > o-EWG > p-EDG > o-EDG > o-EDG+o-R

Question 45

when reacting a Pd catalyst with an Ar-I compound, which reacts faster L2Pd or L1Pd (with bulky ligands)

Answer 45

L1Pd

Question 46

What is significant about cross coupling with ArCl?

Answer 46

can only react if highly activated

Question 47

To activate a reasonably unreactive ArX compound what ligands could you put on the L1Pd?

Answer 47

bulky: John-Phos or tri-tBuphosphine

Question 48

What does the Suzuki coupling do?

Answer 48

Ar-B(OH)2 + ArX --> Ar-Ar

Question 49

How would you improve nucleophile strength in a Suzuki coupling?

Answer 49

use base additives eg CsF, KF, NAOH, NaOMe

Question 50

What is Negishi coupling?

Answer 50

cross-coupling reaction with organozinc - ArZnI + ArX ---> Ar-Ar

Question 51

How do Negishi and Suzuki and Stille coupling compare with regards to functional group tolerance?

Answer 51

Negishi is the least (but most reactive)

Question 52

What type of reagents are used in Stille coupling reactions

Answer 52

(Ar- )Tin (-R3)

Question 53

How would you improve the reactivity of a Stille coupling

Answer 53

add CuCl or LiCl

Question 54

Why would you use Stille over Suzuki or Negishi?

Answer 54

extreme f.g.t. and good for diene synthesis vs biaryl and aryl-alkene synthesis of Suzuki and Negishi

Question 55

What does the sonogashira coupling do?

Answer 55

couples alkynes and X groups using copper species in situ

Question 56

What is Pd catalysed amination?

Answer 56

RRNH + ArX ---> RRN-Ar | only needs mild conditions and has good f.g.t. (weaker base better f.g.t.)

Question 57

applications of Pd-catalysed amination?

Answer 57

cross-coupling secondary amines // primary amine synthesis "ammonia equivalents"

Question 58

what is amidocarbonylation?

Answer 58

substitution of ArX to Ar-C=O(NHR) using a Pd catalyst, CO and RNH2 and base

Question 59

What is the Heck reaction?

Answer 59

complexes alkene to Pd complex, migratory insertion, B-hydride elimination, reductive elimination, oxidative addition

Question 60

What isomer product is preferred from the Heck reaction?

Answer 60

trans - due to the syn elimination

Question 61

what is ring closing metathesis?

Answer 61

way of making cyclic alkenes by combining two alkenes