Retrosynthetic Analysis and Group Interconversions

Question 1

Retrosynthetic analysis

Answer 1

the process of breaking down a target molecule into readily available starting materials by means of imaginary breaking of bonds and by conversion of one functional group to another

Question 2

disconnection

Answer 2

imagined cleavage of a bond to break the molecule into possible starting materials

Question 3

functional group interconversion (FGI)

Answer 3

process of converting one functional group into another e.g. substitution, addition, oxidation or reduction

Question 4

synthons

Answer 4

idealised fragment (cation/anion) resulting from a disconnection

Question 5

synthetic equivalent

Answer 5

reagent carrying out the function of a synthons

Question 6

latent polarity

Answer 6

imaginary pattern of alternating positive and negative charges used to assist in the identification of disconnections and synthons

Question 7

reductions
ketones
esters + carboxylic acids

Answer 7

ketones –> secondary alcohol (NaBH4 or LiAlH4)

esters/carboxylic acids –> primary alcohol (LiAlH4)

Question 8

nones

Answer 8

undergo conjugate addition reactions with appropriate nucleophiles
soft = conjugate e.g. dialkylcuprates
or NaBH4/CuI MeOH - copper makes soft E+ so MeOH can reduce
hard = 1,2 addition e.g. alkyl lithium

Question 9

conjugated unsaturated ketones e.g. dienones

Answer 9

addition may occur further
e.g. Ph2CuLi to a dienone addition occurs at furthest alkene first then a second addition to alkene and reduced carbonyl group

Question 10

LiAlH4

Answer 10

reduces:
ester and acyl chlorides to primary alcohols
ketones to secondary alcohols 
tosylates and alkyl bromides to alkanes
nitriles to primary alkanes
amides to amines

Question 11

NaBH4

Answer 11

reduces:
ketones to secondary alcohols
aldehydes to primary alcohols 
in presence of CuI - 1,4-reduction of enone 
in presence of CeCl3 - 1,2-reduction 
doesn't reduce:
amides
(usually) esters, alkyl halides

Question 12

DIBALH (dis-butyl aluminium hydride)

Answer 12

selective reduction of an ester to an aldehyde
reduction of nitrile to aldehyde
-78 C

Question 13

Oxidation: Jones reagent

Answer 13

Jones reagent : CrO3, H2SO4, H2O
secondary alcohol to ketone
primary alcohol to carboxylic acid

Question 14

Oxidation: PDC (pyridinium dichromate)

Answer 14

protonated pyridine and Cr2O7-
primary alcohol to aldehyde
intramolecular (5-membered ring intermediate)
or intermolecular using pyridinium

Question 15

using protecting group on ketones

Answer 15

acetals
protection = R”OH/ H+
deprotection = H2O/H+

Question 16

protecting groups for alcohols

Answer 16

acetals
silly ethers
esters
ethers

Question 17

protecting alcohol during Grignard reaction

Answer 17

Grignard reagents destroyed by water and acid functional groups
protection = TBDMSCl (tertbutyldimethylsilyl chloride)
deprotection = tBu4NF (TBAF) (strong Si-F bond)

Question 18

RLi

Answer 18

1,2-addition

Question 19

R2CuLi

Answer 19

1,4-addition

Question 20

RMgBr

Answer 20

1,2-addition

Question 21

RMgBr/CuI

Answer 21

1,4-addition

Question 22

NaCH(CO2Et)2

Answer 22

1,4-addition

Question 23

LiAlH4

Answer 23

1,2-addition

Question 24

NaBH4/CuI

Answer 24

1,4-addition

Question 25

NaBH4/CeCl3

Answer 25

1,2-addition

Question 26

RNH2

Answer 26

1,4-addition

Question 27

RSNa

Answer 27

1,4-addition

Question 28

RONa

Answer 28

1,4-addition

Question 29

Baeyer-Villiger OXidation

Answer 29

oxidation of ketones to esters and cyclic ketones and lactones in general substituted between alpha carbon and carbonyl involves alkyl group migration reagent = MCPBA (nucleophile)

Question 30

Beckmann rearrangement

Answer 30

overall insertion of nitrogen next to the carbonyl group to form an amide NH2OH forms oxime (C=NHOH) add H2SO4 (migration of C-C bond) base - amide formed group that migrates is trans to the OH group, mixture of geometric isomers of oxime and amides

Question 31

hydration of double bonds

Answer 31

least substituted: 1. BH3, THF 2. H2O2, NaOH | most substituted: 1. Hg(OAc)2 2. NaBH4

Question 32

addition of HBr to double bonds

Answer 32

``` least substituted (old) : radical mechanism, HBr, H2O2 most substituted (fresh): ionic mechanism, HBr ```

Question 33

electrophilic aromatic substitution

Answer 33

ortho/para: X = Me, NHCOCH3, OH etc | meta: X = NO2, CN, CO2Me etc

Question 34

addition of a nucleophile to an epoxide

Answer 34

most substituted: favoured under acidic conditions (combination of products but major is most sub) e.g. 1. HCl 2. MeOH least substituted: favoured under basic conditions e.g. NaOMe

Question 35

regioselective alkylation of ketones

Answer 35

also use of examines and beta-keto esters base kinetic enolate - least sub (favoured when using low temp and hindered base e.g. LDA) thermodynamic enolate - most sub

Question 36

1,2- and 1,4- dicarbonyl retrosynthesis

Answer 36

mis-matched/dissonant pattern of latent polarities requires reversal of polarity usually associated with the carbonyl group for one of the precursors - unpolung e.g. RO=C- --> dithiane + strong base CH3O=C- --> HCCH (alkyne) + base formyl anion goes to NO2CH3 + base (Henry reaction) RCOHCH2+ --> epoxide RC=OCH2+ --> RC=OCH2Br

Question 37

unpolung

Answer 37

used to describe cases in which a synth of opposite polarity to that normal associated with a required functional group must be used

Question 38

use of dithianes in synthesis

Answer 38

``` HSRSH/H+ (formation) sulphur creates acidic proton because EWG BuLi/THF -78C deprotonates + electrophile hydrolysis of dithiane e.g. Hg2+, H2O CaCO3 MeI, H2O (?) ```

Question 39

use of nitriles in synthesis of alpha hydroxy acids (OH group on alpha carbon of CO2H)

Answer 39

aldehyde + NaCN --> alpha-hydroxy nitrile + H+/H2O --> alpha-hydroxy acid

Question 40

use of nitroalkanes in synthesis of alpha-hydroxy aldehydes

Answer 40

nitroalkane + aldehyde --> Henry reaction to give nitroalcohol 1. NaOH 2. H+ (Nef Reaction) --> alpha-hydroxy alcohol

Question 41

use of nitroalkanes to prepare 1,4 - disubstituted products

Answer 41

nitroalkane + enone (+iPrNH) ---> conjugate addition --> NaOMe = nitronate further - ozonolysis (O3, MeOH) = 1,4-dicarbonyl

Question 42

dehydration of alcohols

Answer 42

H+/H2O alcohols are easy to prepare : RMgBr + RCHO, reduction of carbonyls dehydration may give a mixture, difficult to separate rearrangements commonly occur

Question 43

elimination of alkyl halides

Answer 43

base to give alkene mixture of products often obtained - difficult to separate major product - more substituted C=C because more stable

Question 44

reduction of alkynes

Answer 44

geometry of double bond controlled by selective reduction conditions first: H2, Lindlars cat (5% Pd-CaCO3, Pb(OAc)2, quinoline) gives cis product second: 1. Na, liquid NH3 2. H2O gives trans product

Question 45

preparation of alkyne

Answer 45

substituting H 1. base e.g. BuLi, RMgX - deprotonation 2. electrophile e.g. alkyl halide, aldehyde, epoxide addition of aldehyde gives secondary alcohol addition of epoxide, less hindered end attacked so OH one bond away position of double bond is fixed

Question 46

wittig

Answer 46

R2CO + Ph3P=CH2 phosphonium slide (from salt and base) versatile chemoselective - aldehydes and ketones only regiospecific PhP=O by-product may contaminate product and be difficult to remove resonable control of double bond geometry

Question 47

3 types of slid

Answer 47

reactive - R= alkyl, requires strong base to be formed, (Z) alkenes predominate moderated = R=Ph or vinyl. some stabilisation charge. mixtures stabilised - R=EWG, requires weak base, predominantly E alkenes. only aldehydes