Chem 634 Spring 2013
Nucleophilic Substitution Chemistry
Prof. Donald Watson
"
Assistant Professor"
"
"
Today
a) alcohol activation
b) substitutions at alkyl centers
c) ester formation
d) amide formation
Reading: This week C&S 3.1-3.2, 3.4
Alkyl Nucleophilic Substitution
I assume you understand basic SN1, SN2 and elimination mechanisms.
Common Problem:
OH
Me
Me
Nuc
Nuc
Nuc
Me
Me
OH
(poor leaving group)
Need to activate ROH
Sulfonates
O
O
OH
Me
O
S
Cl
O
R
Me
Me
"py"
N
py
Me
O O
Cl
H O S
R
Me
O
S
Me
R
note retention
Sulfonates
common sulfonates
O
S
O
O
S Me
O
O
S CF3
O
Me
toluenesulfonate
"tosylate" "Ts"
common reagents
O
Cl S
O
Me
(TsCl)
methanesulfonate
"mesylate" "Ms"
trifluoromethanesulfonate
"trifate" "Tf"
MsCl
O
O
F3C S O S CF3
O
O
(Tf2O)
Note alkylOTf are normally unstable
Sulfonates
Recall:
R1
R1
Nuc
LG
Nuc
R2
H
R1
LG
Nuc
H
R2
R2 H
σ*C-LG
transition state
OSO2Me
Me
Me
Nuc
Nuc
SN2
Me
Me
LG
Sulfonates
O
O
S
OH
Me
O
Cl
O
R
Me
Me
O
S
Me
R
retention
"py"
N
OSO2Me
Me
Me
Nuc
SN2
Me
Nuc
overall inversion!
Me
inversion
Alkyl Halides
Formation of alkyl chlorides:
OH
Me
Cl
Me
O
S
Cl
Cl
CH2Cl2, py
O
Me
O
S
Cl
Me
Cl
pyH+
thionyl chloride
Me
Me
+ SO2, pyHCl
Alkyl Halides
Cl
Me
Nuc
Nuc
Me
Me
Me
note: overall rentention
compared to R–OH
Alkyl Halides
Formation of alkyl bromides:
PPh3, Br2
R
OH
R
Br
Alkyl Halides
Formation of alkyl bromides:
Mechanism:
Ph3P
Br Br
Ph3P Br
Br
ROH
Br
R
H
O
R
PPh3
O
- HBr
PPh3
- Ph3P O
Br
Ph3P O
Ph3P O
triphenylphosphine oxide
very thermodynamically favorable
R
Br
Alkyl Halides
Similar reactions for ROH to RX:
X = Br
X = Cl
PBr3
PCl3
O
PPh3 + CCl4
PPh3
+
N Br
N-Bromosuccinimide
"NBS"
O
X=I
PPh3
+
I2
+ imidazole
N
N
H
You need to be able to draw the mechanisms for these reactions.
The Finkelstein Reaction
R
Br
+
NaI
R
I
+
NaBr
not soluble
in acetone
Pg 170 in Kurti & Czako
Reactivity of Alkyl Electrophiles
For RX
TfO>>>>>TsO > I > MsO > Br >> Cl
unstable
sluggish
Most Often Used RX in SN2-type Reactions
Br
Me-I
benzyl bromide
"BnBr"
Cl
allyl chloride
WHY?
Small or activated.
No beta-hydrogen atoms.
NO E2!
Nuc
H
Me
Me
X
How to Control SN2 vs E2
Me
H
Me
X
Nuc
vs
Me
Nuc
SN2
E2
small nucleophiles
“non-basic” nucleophiles
methyl, 1° or 2° substrate
large nucleophiles
“basic” nucleophiles
3° substrates (SN2 very rare)
Note: In most cases, SN2 vs E2 compete.
“Basic” vs “Non-Basic”
MUST KNOW pKa TABLE
(every organic
chemist should know
these)
Note water and
dmso numbers to not
match. Why?
For SN2 vs E2, cutoff is ~ pKa = 12-16
Also see: Evans pKa Table (Harvard)
Reich pKa Table (UW Madison) http://www2.lsdiv.harvard.edu/labs/evans/pdf/evans_pKa_table.pdf
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
Using pka to Predict Equilibrium
Consider:
Treat As:
MeOLi + Bu-H
MeOH + BuLi
MeOH + Bu-
Karxn =?
MeO- + Bu-H
Ignores counter-ion. Not a prefect assumption. In some cases, down right bad, but it gives us a start.
Definitions:
BuH + H2O
MeO-
MeOH + H2O
Ka2
Ka1 = 10-50
Bu- + H3O+
=
+ H3
[MeO-][H3O+]
[MeOH][H2O]
O+
pka1 = 50
Ka2 = 10-17
pka2 = 17
=10-17
Using pka to Predict Equilibrium
Bu- + H3O+
BuH + H2O
BuH + H2O
rewrite: Bu- + H3O+
Ka3
=
[BuH][H2O]
[Bu-][H3O+]
Ka3 = 1/Ka1 =1/10-50
=1/10-50
Using pka to Predict Equilibrium
MeOH + Bu-
[MeO-][BuH]
Karxn =
=
MeO- + Bu-H
= Ka2 • Ka3
[Bu-][MeOH]
[MeO-][H3O+]
[MeOH][H2O]
·
[BuH][H2O]
[Bu-][H3O+]
= 10-17 • 1/10-50
= 10(-17-(-50)) = 1033
Note:
pkaBuLi = 50
pkaMeOH = 17
Alkylation With Carbon Nucleophiles
R
CN
Br
Na+,
–CN
K+
R
CN
pKa 9.4 (12.9)
Note: C–C bond formed
We will see many more carbon nucleophiles later in the class.
Oxygen Nucleophiles
"Williamson Ether Synthesis"
R
OH
pKa (30)
MeI, NaH
pKa' ~36
R
OMe
1° & 2° RX, E2 can compete
OH
Ph
Br
O
K2CO3
pKa 10 (18)
O
Typically solvent is DMF or DMSO
H
NMe2
Me
O
S
Me
Oxygen Nucleophiles
O
R
O
BnBr
OH
Cs2CO3
DMF
R
OBn
Mitsunobu Reaction
DEAD
Me
Me
OH
Me
Me
PPh3, RCO2H
R
O
O
O
DEAD =
EtO
O
N N
OEt
Upsides:
•  works with many acidic nucleophiles
•  clean SN2 chemistry
•  often work when other reactions won't
Downsides:
•  DEAD not overly stable
•  waste
Mitsunobu, Synthesis, 1981,1, 1
Mitsunobu Reaction
Mechanism:
O
O
O
N N
EtO
O
OEt
N N
PPh3
EtO
PPh3
O
EtO
O
O
N N
H
PPh3
OEt
OEt
PPh3
H O
OH
R'
R
O
N N
H
EtO
OEt
HO
O
R"
R'
R"
O
O
EtO
O
N N
H H
waste
OEt
R'
R
O
O PPh3
+
O
R"
O
R'
R
R"
+ OPPh3
waste
Nitrogen Nucleophiles
Classical: Gabriel Synthesis
O
NK
O
+
R
R
Br
+ KBr
N
O
O
O
H2N NH2
R
NH2
+
2 steps
HN
HN
O
Nitrogen Nucleophiles
Azides
Me
Me
Br
NaN3
pKa' 7.9
Me
Me
[Red]
Me
N3
Caution!:
•  NaN3 ~1000x more toxic than NaCN
•  Azides can explode
Me
NH2
Nitrogen Nucleophiles
Amides
soft
O
R
O
MeI
NHEt
Cs2CO3
DMF
O
MeO S OMe
O
dimethyl sulfate
LiAlH4
N Et
Me
R
hard
OMe
R
NMe
"imidate"
R
N Et
Me
Carboxylate chemistry
O
O
R
OR
R
O
NR2
R
Cl
Esters
Fisher Esterification
O
+
R
OH
O
R
O
HCl, heat
MeOH
R
H
O
R
OH
H
OMe
O
H
OH
OMe
OH
OMe
H
MeOH
Cl
HCl
OH2
R
OH
OMe
– H2O
O
R
H
OMe
Cl
O
R
OMe
Note: Reaction is an equilibrium process driven by concentrations.
Esters
Transesterification
O
R
+
OMe
EtOH
O
H+, heat
R
OEt
Esters
Activation by Acid Chloride
O
O
R
Cl
Cl
O
O
OH
R
(oxalyl chloride)
Cl
-HCl, CO, CO2
Cl
Cl
O
R
O
O
O
H
O
O
Cl
O
R
O
H
O
O
Cl
O
R
O
O
Cl
Cl
Also works with thionyl chloride (SOCl2), etc.
Cl
O
R
Cl
O
O
Esters
Reaction of acyl chlorides with alcohols:
O
+ BuOH
R
Cl
O
O
Cl
R
OBu
H
Et3N
Et3N
R
Cl
OBu
O
R
OBu
Esters
Acyl Transfer Catalysis
NMe2
(DMAP)
O
+ Nuc
R
O
N
Et3N
Cl
R
O
R
Nuc
O
Cl
N
R
N
NMe2
Nuc
NMe2
speeds reaction
N
Related: HOBT for peptide coupling.
N
N
OH
Esters
Mixed Anhydrides – Yamaguchi Lactonization
Cl
O
Cl
HO
OH
n
Cl
O
Cl
O
DMAP
n-3
O
via:
OH
O
O
O
+
Cl
Cl
Cl
Cl
O
OH
Cl
Good for large ring synthesis.
Cl
Esters
Diazo methane (methyl esters only)
H
N
N
C
N
N
H
H
H
N
N
O
R
H
OH
O
H
+
R
O
N2
CH3
O
R
OMe
CAUTION! CH2N2 explodes very easily, need special glassware.
Amides
From Acids:
O
O
+
R
BuNH2
OH
R
O
+
BuNH3
Amides not formed except under very forcing conditions.
From Esters:
O
O
+
R
OMe
BuNH2
+ MeOH
R
NHBu
Amide formation can work with small, nucleophilic amines and
non-sterically hindered esters, but often requires heat.
Amides
Classic: Schotten-Baumann
O
R
+
Cl
BuNH2
O
NaOH
or Et3N
R
NHBu
+ H2O/NaCl
or Et3NHCl
Note: Amines nucleophilic enough rxn can be run in water.
Amides
Carboimide Couplings
DCC =
BuNH2
O
R
OH
O
DCC
O
+
R
NHBu
CyHN
NHCy
Et
EDCI =
Mechanism:
H
R
R
N C N
NMe2
B
O
N C N
N C N
R
O
R
R
N
O
O
NR
R
OH
O
R
R
O
O
NH
R
NR
O
NHR2
RHN
NR
NHR2
H
R
O
N
HB
NR
Amides
Many
Similar
Methods:
N
Me
Mukayama, TL, 1970, 1901
HNMe2
O
R
Cl
O
NMe2
Py
N
Me
Cl
R
R
pyridine
OH
Mechanism:
O
O
R
OH
Aromaticity broken
H
O
O
H
R
N
Me
O
R
Me2NH
O
O
N
Me
R
O
N
Me
Py
H
+
NMe2
O
N
Me
Amides
AlMe3 Activation
HNR2
O
R
OMe
AlMe3
O
+
R
NR2
Me2Al OMe
Likely via:
AlMe3 + HNR2
O
Me2Al NR2
Good for Weinreb Amides:
Me
Me
R
OMe
N
Me
Al
O
R
NMe2
OMe
Weinreb (Penn State), TL, 1977, 4171