Download Chap20 Grignard reagents

Grignard reagents & Reducing reagents
R X
Mg°/THF or Et 2O
2/22/2016
E+
R Mg X
+Mg
O
δ+
H OR'
E+ =
R–
R E
R δ+ R' R δ+ OR2
O
H 3C
Mg°, THF
Br
A.
R
Open Here
X
For example:
O
O R2 ≠ H
CH 3
MgBr
H 3C
H 3C
H+
O—
OH
CH 3
CH 3
I
B.
1) Mg°, Et 2O
D
2) D 2O
I
C.
HO
1) Mg°, Et 2O
Ph
O
2)
MeO
Note 1: NH 4Cl is a weak acid used
to quench the alkoxide
Note 2: When using esters assume
excess Grignard reagent is used
Ph
3) NH 4Cl
The mechanism for Grignard reagent addition to esters:
O
O
Me MgBr
MeO
H
– OMe
MeO
Et
Me
the tetrahedral
intermediate
Et
O
Me
O
H
O
Et
Me
OH
Et
Me
Me
Et
Me
Me MgBr Note: In the tetrahedral intermediate,
you can kick out OR, Cl, or other
common leaving group. You cannot
Note: Grignard reagents add to aldehydes faster
have an alkyl (R) group or hydrogen as
than to ketones Grignard reagents add to ketones
the leaving group
much faster then to esters
Using Grignard reagents to synthesize alcohols:
Nearly all carbon-carbon bonds at an alcohol functional group could
be prepared using Grignard technologies.
OH
Me
OH
Me
BrMg
O
Me
Br
+
H
BrMg
or
O
MeMgBr
+
H
OH
H
H
+
And because you can
make aldehydes from
alcohols...
O
H
H
Grignard reagents & Reducing reagents
2/22/2016
Retrosynthetic analysis tips:
OH
R
R
comes
R
O
+
RMgBr
OR
R
from
Cl
RMgBr +
MeO
O
OMe
R =R =R
OH
R
R
R1MgBr
R1
O
+
R
R
OH
R
O
R1
O
RMgBr +
OR
R1
Cl
Note: OMe represents
any ester
R =R
R
RMgBr +
MeO
OR
R1MgBr
R1
2
O
+
R
O
R2
Then
R
H OH
R2
R2
H
R2
R
O
+
RMgBr
For Example:
O
OH
Me
MeO H
O
H
O
+
O
MeO H
O
Me
O
ClMg
H
O
Three last notes on Grignard reagents:
1) Grignard reagents are nucleophiles that add to the specific types of electrophiles shown in
this handout (ie. that are not generally used for SN 2 reactions on alkyl halides).
2) Alkyl Na, Li, and K reagents (i.e. H 3CC CNa ) react very similarly to Grignard reagents.
3) An R – addition to a carbonyl is a reduction just like a hydride H – delivered from BH 4—
H2
Reducing Reagents
Na, Li, or K : Used to reduce alkynes to trans-alkenes
BH 3 : Adds to alkenes and alkynes (reducing them)
With the CBS Catalyst, reduces ketones to alcohols, enantioselectively
Selectively reduces carboxylic acids to alcohols (Does react with esters)
NaBH 4 : Reduces aldehydes, acid chlorides, and ketones to the corresponding alcohol (reduces esters very slowly)
LiBH 4 : Reduces esters, ketones, acid chlorides, and aldehydes to the corresponding alcohol
LiAlH([OC(CH 3)3]3 : Used to reduce acid chlorides and esters (at –78 °C) to aldehydes (stops at the aldehyde!)
Reduces ketones, acid chlorides,and aldehydes to the corresponding alcohol
i-Bu2AlH (DIBAL): Used to reduce esters and acid chlorides (at –78 °C) to aldehydes (stops at the aldehyde!)
Reduces ketones, acid chlorides,and aldehydes to the corresponding alcohol
LiAlH 4 : (LAH) Very powerful reducing agent also reduces carboxylic acids
Reduces ketones, acid chlorides,and aldehydes to the corresponding alcohol
Reduces amides to the corresponding amine