651.06
Nucleophilic Addition To Carbonyls O R
! !
Lewis basic site-reacts with electrophiles
O Y
R
electron-deficient carbon-reacts with nucleophiles
Y
overall reaction:
E+ O
Nuc:
O
Nuc
E
R
R
this can occur by either of three mechanisms: E+ O
1) Nuc:
or
2)
Nuc
R
R
O
:Nuc
R
or
3) R
O
Nuc R
_ +
Nuc
E
O
R
_ :Nuc
O
simultaneous
E
E+
:O:
E
O
E
R
O
electrophilic attack
E Nuc R
nucleophilic attack
which mechanism is operative will depend on electrophilicity of E+, and nucleophilicity of Nuc: general rule: when E+ is H+ or strong Lewis acid, Nuc is neutral ⇒ choose mechanism #2 when E+ = Li+, Na+, K+ ; Nuc is anionic ⇒ mechanism #1 when E+ = R4N+ ; Nuc is anionic ⇒ mechanism #3
234
651.06
Case study - hydration of carbonyls: O
+
H2O
R'
R
HO
OH
R
R'
normally Keq (ketones < 10-5) (aldehydes 10-3 to 103) Ex: O
+ H
CCl 3
HO
H2O
Cl3 C
OH
Keq = 3 x 104
H
Why do EWG’s favor hydrates?
Kinetics of hydration k1 ( + H2O)
O R
H
HO
OH
R
H
(- H2O) k-1
How to measure k1? Look at carbonyls with Keq
O R
R'
>
O R
SR'
>
O
O
R
OR'
>
R
NR2
(based on electronegativity and π - donation of Y) Mechanism #1 - saponification
O
R
NaOH OR'
H2O
O R
O
OH OR
- OR
246
R
O
NaOH O-H
R
O
651.06 Mechanism #2 - Fischer esterification
H H
O
HCl
R
+
MeOH
OH
R
MeOH
O-H R
OMe
H
O
OH
-H
O
R
H
O
OMe
O-Me
R
OH
+H
-H
OH
OMe
- H2 O
R
OH2
an alternative mode of catalysis - nucleophilic catalysis O
OH Cl
very slow reaction (t
+ O
> 24h)
O
OH Cl
1/2
N
O
+
(t1/2 ~ 1h)
Why does pyridine accelerate the reaction? it’s not going to deprotonate cyclohexanol (Keq = 105-17 = 10-12) So, look at alternative mechanisms: O
O
N Cl
Cl
O
N
N
A OH
O
O O
H
O H
247
O
O N
651.06 So why is this any faster? reason 1: pyridine is a far better nucleophile than an alcohol reason 2: acyl pyridinium ion A is far more reactive than the acyl chloride (Why? better leaving group) ⇒ combine better nucleophilicity with better leaving group ability & you have nucleophilic catalysis
NMe2
better nucleophilic catalysts than pyridine:
N
(DMAP), PBu3
(NEt3 also used)
Conjugate (1,4) Addition 1
O
!," - unsaturated carbonyl compounds have 2 sites of attack by nucleophiles: C-2 or C-4 (C ")
2 3
Nuc
4
Addition to Cβ is referred to as 1,4-addition (conjugate addition): O
O
O
H Nuc
Nuc
Nuc
What factors govern 1,2- vs. 1,4 - addition? O
Nuc
O
Nuc
Nuc
Nuc
1,4
1,2
O
alkoxide (less stable)
enolate (more stable) thermodynamic product
kinetic product
248
651.06 Why is 1,2-adduct the kinetic product? look at transition states
!
O
E
O
O
E
E
Nuc Nuc
A
unless there is a high concentration of E+, 1,4-addition is slower in general Examples of 1,4 - additions: O
O HCN
(note, not NaCN or KCN
or Et2 AlCN
reversible reactions
NC O
O
MeO2C
CO2Me "Michael Addition" Org. React., 1959, 10, 179
MeO2C
NaOMe, MeOH
CO2 Me O
O
SiMe3 "Sakurai reaction" Sakurai, JACS, 1977, 99, 1673
TiCl4
Why 1,4 - addition? O
Cl
O
TiCl3
Cl
O
TiCl3
TiCl4
no longer a cyclic transition state, so 1,2 & 1,4 are kinetically similiar
SiMe3 Cl
249
OTiCl3
O
651.06 One major category of 1,4 - additions is the addition of organocuprate reagents to α, β − unsaturated carbonyl compounds: O O
LiCuMe 2 Gilman's reagent How does this work & why does it give 1,4 - addition? - all organocopper reagents are CuI species - free radicals so, probably the mechanism involves free radical intermediates: JACS, 1994, 116, 2902-2913
1,2 vs. 1,4 Addition
HO
O R
Ph
R'
OH
R'
R'-M
+ R
Ph
R
Ph
R
R’
M
1,2 addition
1,4 addition
i-Pr
Me
MgCl
50
50
t-Bu
Me
MgCl
67
33
i-Pr
Ph
MgCl
34
66
t-Bu
Ph
MgCl
33
67
t-Bu
Me
Li
85
15
250
