Nucleophilic Substitution & Elimination Chemistry
Beauchamp
1
Available chemicals f rom the catalog (the starting sources of carbon compounds will continually decrease as we learn new reactions.
Sources of carbon - you can invoke these whenever needed:
CH4
Sources of carbon - you can until we cover reactions that will make them f rom the above
compounds, then they will go away:
HO
Br
HO
Br
OH
OH
Br
Br
Br
HO
OH
Br
Br
Br
Br
Br
Br
Commercially available chemicals and reagents - you can invoke these whenever you need them.
Br2
bromine
Cl2
chlorine
HCl
hydrogen
chloride
Salts / ionic substances
Na
Na
H
S
H
O
sodium
sodium
hydroxide hydrogen
sulf ide
HBr
HI
H2SO4
H2O2
OH
HNO3
H2 O
H3PO4
NH3
CO2
hydrogen hydrogen sulf uric phosphoric nitric acid water ammonia hydrogen
carbon dioxide
bromide
iodide
acid
acid
peroxide
t-butyl alcohol
(use to make
Na
t-butoxide)
Na
H
Na
Cl
O
O
sodium hydride
Na
Na
NHR2
N
N
N
N
(very strong base)
Br
Cu
sodium azide
R = C or H
N
C
Na
Br
Na
(excellent nucleophile)
sodium amide
H K
sodium nitrite
cuprous
sodium
(very strong base)
bromide
cyanide
potassium hydride
HgX2
Na
IH
(very strong base)
H
(mecuric salts)
H
H
H Al H Li
H B CN
Na
H
H
H
Li
Li
lithium aluminumhydride = LAH sodium cyanoborohydride
sodium borohydride
n-butyl lithium
phenyl lithium
(nucleophylic hydride) (very strong nucleophilic hydride) (nucleophylic hydride)
(very strong base
(very strong base)
(LiAlD4 too)
or nucleophile, use
(NaBD4 too)
Lewis acids
anytime)
O O
O
O
AlBr3
O
O
O
pre aldehydes/ketones
FeBr3
Mn
Os
BF3
O
O O
O
S
SOCl
N H
2
K
OH
ketone
N
potassium permanganate
PBr3
O
O
ethanoic acid
N
(a carbonyl)
osmium tetroxide
SO3
a carboxylic acid)
H
Br2
S
pre alds / kets
phthalimide O
diisopropylamine
pre
alds
/
kets
etc.
dithiane
Br
(an imide)
O
Cl
O
O
O
NBS = N-bromosuccinimide
O
Cl S
O
O
Cr
(supplies
f
ree
radical
bromine
Cr
H
3 ozone
f or allylic & benzylic substitution)
O
O
O
O
O
O O
pyridine
reactions
H2O / H3O+
= Ts-Cl (tosyl chloride)
meta chloroperbenzoic acid
(PCC)
(Jones)
makes ROH into tosylates
HCCl3
(mCPBA)
1. O3, -78oC
Ph
CH2I2
chlorof orm
diborane
2. CH3SCH3
diborane
1. Hg(OAc)2/H2O
N = py
Zn / Cu
P
Ph
use w/ alkenes use w/ alkenes
2. NaBH4
Simmons
H
o
H
1. O3, -78 C
pyridine =
HCBr3
Ph
Smith
1.
1.
B H
proton sponge
H
B
2.
NaBH
bromof
orm
1. Hg(OAc)2/ROH
4
triphenylphosphine
reagent
H
H
(to make Wittig salts)
2. NaBH4
dialkylborane
2. H2O2/HO
2. Br2/CH3O
1. O3, -78oC
use w/ alkynes
Various metals
2. H2O2, HO
R
NH
1.
Pd
/
H
Mg
NH
Pd
/
H
Li
B H
Na / NH3
Na
2
2
Zn
OH H N
2
HO
2
magnesium lithium sodium in ammonia zinc palladium &
quinoline
R
pyrrolidine
hydrazine
ethylene
metal
metal metal (Birch reagent) metal
hydrogen
2. H2O2/HO
(Lindlar's cat)
(Wolf f -Kishner) (enamines)
glycol
O
(protect C=O)
THP
toluene sulf onic acid = TsOH
HO S
(protect O-H)
O
(very
strong
organic
acid)
O
CH2
H B H
H3C Li
methyl lithium
(very strong base)
C
Na
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Nucleophilic Substitution & Elimination Chemistry
Beauchamp
2
C1 through C7 R-Br examples (no stereochemistry indicated; enantiomers and diastereomers). Soon any of these will
be within our grasp (…and more).
1C
2C
3C
Br
4C
Br
Br
Br
Br
H3C
Br
Br
Br
5C
Br
Br
Br
Br
Br
Br
Br
Br
6C
Br
Br
Br
6C
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
6C
Br
Br
Br
Br
7C
Br
Br
Br
Br
Br
Br
7C
Br
Br
Br
Br
Br
Br
7C
Br
Br
Br
Br
Br
Br
7C
Br
Br
Br
Br
Br
Br
Br
Br
Br
7C
Br
Br
Br
Br
7C
Br
Br
Br
Z:\files\classes\315\315 Handouts\available chemicals, syn targets & chem catalog.doc
Br
Br
Br
Br
Br
Nucleophilic Substitution & Elimination Chemistry
Beauchamp
3
Group A (bromo compounds from free radical substitution at sp3 C-H positions, from alcohols and alkenes)
Br
make
various ways
given until
alkenes
Br
Br
Br
Br
Br
Br
H3C
Br
Br
Br
Br
Br
Group C (ROH from methyl and primary bromides and hydroxide via SN2 reactions; ROH from secondary
and tertiary bromides and water via SN1, but rearrangements are possible; also ROH from alkenes,
carbonyls and epoxides)
OH
make
various ways
OH
OH
OH
OH
OH
OH
H3C
OH
OH
OH
OH
OH
Group D (esters from methyl, primary and secondary bromides and carboxylates (acetate, here) via SN2
reactions, esters can be hydrolyzed to alcohols via acyl substitution with hydroxide, and via SN1 at tertiary
RX and various other methods we will learn)
Group F (ethers from methyl and primary bromides and alkoxides via SN2 reactions, t-butoxide reacts mostly
by E2, 2o RX and 3o RX mainly form E2 products too) (ethers from secondary and tertiary bromides and
alcohols via SN1, but rearrangements are possible)
Z:\files\classes\315\315 Handouts\available chemicals, syn targets & chem catalog.doc
Nucleophilic Substitution & Elimination Chemistry
Beauchamp
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Epoxides are “special” ethers that can be made from bromohydrins + base or alkenes + mCPBA (later). The large
ring strain allows them to be easily opened by strong nucleophile/bases or in strong acid.
Group G (amines from methyl, primary and secondary bromides and conjugate base of phthalimide via SN2
reactions, the alkyl imide can be hydrolyzed to primary amines via two acyl substitutions with hydroxide,
see mechanism above) or make azides via SN2 reactions and then react using 1. LiAlH4, 2. workup.
Group H (tosylates formed from alcohols and tosyl chloride/pyridine via acyl substitution reaction, converts
“OH” from poor leaving group into a very good leaving group similar to iodide)
OTs
H3C
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
Group I (alkenes formed by E2 reaction with potassium t-butoxide and R-Br compounds or make via E1
reactions of ROH and H2SO4/)
Group J (make ethyne or propyne using dibromo ethane or propane and double E2 reactions using NaNR2), ( make
other alkynes from terminal acetylide and methyl or primary RX via SN2 reaction; two reactions are possible in
stepwise manner on both sides of ethyne, can put one or two “R” groups on, mostly E2 reaction at 2o R-Br and only E2
at 3o RX), can use zipper reaction to move alkyne to end position along unsubstituted linear chain and start over.
Z:\files\classes\315\315 Handouts\available chemicals, syn targets & chem catalog.doc
Nucleophilic Substitution & Elimination Chemistry
Beauchamp
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Group K (nitriles from cyanide and methyl, primary and secondary RX via SN2 reaction, reaction, only E2
reaction at 3o R-Br; or make from primary amides + SOCl2)
Group L (thiols from hydrogen sulfide and methyl, primary and secondary RX via SN2 reaction, reaction,
only E2 reaction at 3o R-Br in our course), Can do reaction a second time and make sulfides, R1-S-R2.
SH
SH
SH
SH
SH
SH
H3C
SH
SH
SH
SH
SH
R
R
S
H3C
S
S
R
R
S
S
S
R
R
S
R
S
S
R
S
R
S
R
Group M (synthesis of ketones from 2-propanone (acetone) via SN2 with propanone enolate at methyl, 1o,
2o RX. Only E1 at 3o RX. Make propanone enolate from propanone and lithium diisopropylamide =
LDA at –78oC, made from diisopropylamine and n-butyl lithium shown on page 2 under useful acid/base
reactions.)
Z:\files\classes\315\315 Handouts\available chemicals, syn targets & chem catalog.doc
Nucleophilic Substitution & Elimination Chemistry
Beauchamp
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Group N (synthesis of esters from ethyl ethanoate (ethyl acetate) via SN2 using an ester enolate at methyl, 1o, 2o RX.
Only E1 at 3o RX. Make ester enolate from ester and lithium diisopropylamide = LDA at –78oC, made from
diisopropylamine and n-butyl lithium shown on page 2 under useful acid/base reactions.)
R
N
Li
O
LDA = lithium diisopropylamide
O
O
acid/base
rxn
H
R
SN 2
rxn
1
O
R
ethyl ethanoate
ethyl acetate
O
X
R
O
-78oC
O
carbanion nucleophile
O
new bond
O
O
O
These are examples
there are other
possibilities.
O
O
O
O
O
O
O
Make carbonyl compounds from alcohols (aldehydes (PCC), ketones (PCC or Jones) and carboxylic acids
(Jones). There are many other methods too.
aldehydes
O
O
O
O
O
O
H
H
H
H
H
H
O
H
H
carboxylic acids (remember these can be made into esters)
O
O
O
O
O
O
OH
H
OH
OH
OH
OH
O
OH
OH
O
ketones
O
O
O
O
Make acid chlorides from carboxylic acids + thionyl chloride (SOCl2). Acid chlorides can be made into
many things including esters, amides and anhydrides (for now).
Z:\files\classes\315\315 Handouts\available chemicals, syn targets & chem catalog.doc