Retrosynthetic Analysis and Group Interconversions Flashcards
Retrosynthetic analysis
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
disconnection
imagined cleavage of a bond to break the molecule into possible starting materials
functional group interconversion (FGI)
process of converting one functional group into another e.g. substitution, addition, oxidation or reduction
synthons
idealised fragment (cation/anion) resulting from a disconnection
synthetic equivalent
reagent carrying out the function of a synthons
latent polarity
imaginary pattern of alternating positive and negative charges used to assist in the identification of disconnections and synthons
reductions
ketones
esters + carboxylic acids
ketones –> secondary alcohol (NaBH4 or LiAlH4)
esters/carboxylic acids –> primary alcohol (LiAlH4)
nones
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
conjugated unsaturated ketones e.g. dienones
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
LiAlH4
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
NaBH4
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
DIBALH (dis-butyl aluminium hydride)
selective reduction of an ester to an aldehyde
reduction of nitrile to aldehyde
-78 C
Oxidation: Jones reagent
Jones reagent : CrO3, H2SO4, H2O
secondary alcohol to ketone
primary alcohol to carboxylic acid
Oxidation: PDC (pyridinium dichromate)
protonated pyridine and Cr2O7-
primary alcohol to aldehyde
intramolecular (5-membered ring intermediate)
or intermolecular using pyridinium
using protecting group on ketones
acetals
protection = R”OH/ H+
deprotection = H2O/H+
protecting groups for alcohols
acetals
silly ethers
esters
ethers
protecting alcohol during Grignard reaction
Grignard reagents destroyed by water and acid functional groups
protection = TBDMSCl (tertbutyldimethylsilyl chloride)
deprotection = tBu4NF (TBAF) (strong Si-F bond)
RLi
1,2-addition
R2CuLi
1,4-addition
RMgBr
1,2-addition
RMgBr/CuI
1,4-addition
NaCH(CO2Et)2
1,4-addition
LiAlH4
1,2-addition
NaBH4/CuI
1,4-addition
NaBH4/CeCl3
1,2-addition
RNH2
1,4-addition
RSNa
1,4-addition
RONa
1,4-addition
Baeyer-Villiger OXidation
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)
Beckmann rearrangement
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
hydration of double bonds
least substituted: 1. BH3, THF 2. H2O2, NaOH
most substituted: 1. Hg(OAc)2 2. NaBH4
addition of HBr to double bonds
least substituted (old) : radical mechanism, HBr, H2O2 most substituted (fresh): ionic mechanism, HBr
electrophilic aromatic substitution
ortho/para: X = Me, NHCOCH3, OH etc
meta: X = NO2, CN, CO2Me etc
addition of a nucleophile to an epoxide
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
regioselective alkylation of ketones
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
1,2- and 1,4- dicarbonyl retrosynthesis
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
unpolung
used to describe cases in which a synth of opposite polarity to that normal associated with a required functional group must be used
use of dithianes in synthesis
HSRSH/H+ (formation) sulphur creates acidic proton because EWG BuLi/THF -78C deprotonates \+ electrophile hydrolysis of dithiane e.g. Hg2+, H2O CaCO3 MeI, H2O (?)
use of nitriles in synthesis of alpha hydroxy acids (OH group on alpha carbon of CO2H)
aldehyde + NaCN –> alpha-hydroxy nitrile + H+/H2O –> alpha-hydroxy acid
use of nitroalkanes in synthesis of alpha-hydroxy aldehydes
nitroalkane + aldehyde –> Henry reaction to give nitroalcohol
1. NaOH 2. H+ (Nef Reaction) –> alpha-hydroxy alcohol
use of nitroalkanes to prepare 1,4 - disubstituted products
nitroalkane + enone (+iPrNH) —> conjugate addition –> NaOMe = nitronate
further - ozonolysis (O3, MeOH) = 1,4-dicarbonyl
dehydration of alcohols
H+/H2O
alcohols are easy to prepare : RMgBr + RCHO, reduction of carbonyls
dehydration may give a mixture, difficult to separate
rearrangements commonly occur
elimination of alkyl halides
base to give alkene
mixture of products often obtained - difficult to separate
major product - more substituted C=C because more stable
reduction of alkynes
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
preparation of alkyne
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
wittig
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
3 types of slid
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
