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Important Synthetic Technique: protecting
groups. Using Silyl ethers to Protect Alcohols
Protecting groups are used to temporarily deactivate a functional group while
reactions are done on another part of the molecule. The group is then restored.
Example: ROH can react with either acid or base. We want to temporarily
Silyl ether. Does
render the OH inert.
not react with non
Sequence of Steps:
aqueous acid and
bases or moderate
Et3N
aq. acids and
1. Protect:
ROSiR'3
ROH + Cl-SiR'3
bases.
2. Do work:
Alcohol group protected, now do desired reactions.
Bu4N+ F-
3. Deprotect: ROSiR'3
ROH + F-SiR'3
THF
Now a practical example. Want to do this transformation which uses the very basic
acetylide anion:
Replace the H with C2H5
Want to employ this general reaction sequence which we have used before to
make alkynes. We are removing the H from the terminal alkyne with NaNH2.
R'Br
NaNH2
R
H
R
:
R
R'
Problem in the generation of the acetylide anion: ROH is stronger acid than
terminal alkyne and reacts preferentially with the NaNH2!
Solution: protect the OH (temporarily convert it to silyl ether).
Most acidic proton.
Perform desired
reaction steps.
Protect,
deactivate OH
Remove
protection
Alcohol group
restored!!
Revisit Epoxides. Recall 2 Ways to
Make Them
H
Note the
preservation of
stereochemistry
peroxyacid
RCO3H
H
H
H
Epoxide or
oxirane
OH
H
base
H
Cl2
H2O
H
+ enantiomer
H
Cl
anti addition
chlorhydrin
O
Use of Epoxide Ring, Opening in Acid
In acid: protonate the oxygen, establishing the very good leaving group. More
substituted carbon (more positive charge although more sterically hindered) is
attacked by a weak nucleophile.
H
CH3OH
O
H
H
HO
H
CH3
H CH3
H2SO4
H
H
Very similar to opening of
cyclic bromonium ion.
Review that subject.
OCH3
Due to
resonance,
some positive
charge is
located on
this carbon.
Inversion
occurs at this
carbon. Do you
see it?
Classify the
carbons. S
becomes R.
Epoxide Ring Opening in Base
In base: no protonation to produce good leaving group, no resonance but the ring
can open due to the strain if attacked by good nucleophile. Now less sterically
hindered carbon is attacked.
CH3OO
H
H
H
H
OH
H
H
CH3
H3CO
A wide variety of synthetic uses can be made of this reaction…
CH3
Variety of Products can be obtained by varying the nucleophile
Do not memorize
this chart. But be
sure you can figure
it out from the
general reaction:
attack of
nucleophile in
base on less
hindered carbon
H2O/ NaOH
Attack
here
1.
2.
OH
LiAlH4
H2O
An Example of Synthetic Planning
Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably
follow a useful pattern.
:Nu
The epoxide
ring has to have
been located
here
OH
O
Nu
The pattern to be
recognized in the
product is
–C(-OH) – C-Nu
This bond was
created by the
nucleophile
Synthetic Applications
nucleophile
Realize that the H2NCH2- was
derived from nucleophile: CN
N used as
nucleophile
twice.
Formation of
ether from
alcohols.
Epichlorohyrin and Synthetic Planning, same as
before but now use two nucleophiles
Observe the pattern in the product
Nu - C – C(OH) – C - Nu. When you observe
this pattern it suggests the use of epichlorohydrin.
Both of these bonds will be
formed by the incoming
nucleophiles.
Preparation of Epichlorohydrin
Try to anticipate the
products…
OH
Cl2 / H2O
Cl2, high temp
O
base
ClH2C
Cl
Recall
regioselectivity for
opening the cyclic
chloronium ion.
Cl
Cl
Sulfides
Preparation
Symmetric R-S-R
Na2S + 2 RX

Unsymmetric R-S-R’
NaSH + RX
 RSH
RSH + base  RS –
RS- + R’X  R-S-R’
R-S-R
Oxidation of Sulfides
O
S
NaIO4
H2O2 or NaIO4
S
sulfide
O
S
sulfoxide
O
sulfone
Organometallic Compounds
Chapter 15
Carbon Nucleophiles: Critical in making larger organic molecules.
Review some of the ones that we have talked about….
Cyanide ion: CN- + RX

RCN
 RCH2NH2
Synthetic thinking: Disconnect
+
NH2
CN-
Br
Acetylide anions:
strong base
RC
CH
RX
RC
RC
C:
CR
Synthetic Thinking: This offers many
opportunities provided you can work with the
two carbon straight chain segment.
Ph
X
Ph
Ph
Ph
Ph
Ph
Enolate anions:
O
or
base
O
X
O
O
OEt
H
RX
O
O
OEt
OEt
H
H
R
Try to see what factors promote the formation of the negative charge on the
carbon atoms: hybridization, resonance.
We examine two types of organometallics: RMgX, a Grignard
reagent, and RLi, an organolithium compound
Preparation
d-d+
dd+
Solvated by ether, aprotic solvent
Basicity
Recall that a carbanion, R3C:-, is a very strong base.
So also Grignards and alkyl lithiums.
Ethane, a gas.
Bottom Line: Grignards are destroyed by (weak) protic acids: amines,
alcohols, water, terminal alkynes, phenols, carboxylic acids. The
Grignard, RMgX, is converted to a Mg salt eventually and RH.
The liberation of RH can serve as a test for protic hydrogens.
Reactivity patterns
Recall the SN2 reaction where the alkyl group, R, is part of the electrophile.
Nucleophile
Nucleophile
Nu:- + R-X
Nu - R + X-
Electrophile
Forming the Grignard converts the R from
electrophile to a potential nucleophile. A wide
range of new reactions opens up with R as
nucleophile.
- +
RX + Mg  R-Mg-X
Electrophile
Electrostatic potential
maps.
+
-
Recall Reactions of Oxiranes
with Nucleophiles
Recall opening of oxirane with a strong, basic nucleophile.
CH3OO
H
H
H
H
OH
H
H
CH3
H3CO
CH3
The next slides recall the diversity of nucleophiles that may be used.
Observe that there is limited opportunity of creating new C-C bonds, welding
together two R groups. We seem to be somewhat lacking in simple
carbon based nucleophiles.
Recall Synthetic Applications
nucleophile
Only reaction with the acetylide
anion offers the means of making
a new C-C bond and a larger
molecule. Problem is that a
terminal alkyne is needed.
A Grignard has a reactive, negative carbon. Now examine reaction of
Grignard and oxirane ring.
Net results
Newly formed bond
The size of the alkyl group has increased by 2. Look at this alcohol to alcohol
sequence
R-OH  R-X  R-Mg-X  R-CH2-CH2-OH.
The functionality (OH) has remained at the end of the chain. We could make it
even longer by repeating the above sequence.
Note attack on less
hindered carbon
Now a substituted oxirane…
Newly formed bond
Synthesis Example
Retrosynthesize the following
OH
OH
O
CH2CH=CH2
CH2=CH - CH2MgBr
Recall reaction of a nucleophile with an
(oxirane) epoxide to give a
HO-CC-Nu pattern. Back side attack gives
anti opening.
Trans geometry suggests trying an
oxirane. What should the nucleophile
be?
The allyl group should be the
nucleophile. This is done by using a
Grignard (or Gilman).
Gilman Reagent (Lithium
diorganocopper Reagents)
Li
R-X
Preparation of Gilman Reagents
CuI
R-Li
R2CuLi
Gilman
Reactions of Gilman Reagent
Coupling Reaction Used to create new C – C
bonds..
Overall result. R-X + R’-X    R – R’
Necessary details
Li
As before:
Next step:
CuI
R-Li
R-X
R2CuLi
electrophile
R'-X
R2CuLi
R - R'
Restrictions on the process. Caution.
R group which goes
into Gilman may be
methyl, 1o (best not 2o
or 3o), allylic, vinylic
(unusual), aryl
Alkyl (not 3o), vinylic
nucleophile
Particularly useful, reaction with
vinyl halides to make an alkene.
trans
Note that the stereochemistry of the alkene is
retained.
Gilman and oxiranes
1. R2CuLi
HO
O
2. H2O, HCl
R
R of the Gilman reagent is the nucleophile, typical of organometallics.
Because in basic media (acid destroys Gilman) oxygen of oxirane can not
be protonated. Less hindered carbon of oxirane is attacked.
Synthetic Analysis
Similar to Grignard
analysis.
1. R2CuLi
HO
O
2. H2O, HCl
R
Newly formed bond.
Note its position
relative to the OH.
Example of Retrosynthetic Analysis
Design a synthesis using oxiranes
The oxirane ring could be
on either side of the OH.
Look at both possibilities.
Ph
Nucleophile can come in
on only one position of
oxirane, on the C to which
the OH should not be
attached…
OH
OH
OH
or
Ph
On the left, located here.
Open oxirane here.
Nucleophile makes this bond.
Ph
On the right, located here.
Open oxirane here.
Nucleophile makes this bond.
O
(PhCH2)2CuLi
2 synthetic routes
available
O
Ph
LiCu(CH2CH3)2
Synthesis Example
Carry out the following transformation in as many steps as needed.
Br
O
OCH3
O
target
OH
Br
O
OCH3
Remember
oxidation of a
secondary
alcohol can
produce a
ketone.
OCH3
Note pattern of a
nucleophile
(OCH3) then CC then OH. Use
an epoxide.
Epoxides
can come
from alkenes
via peracids.
Alkenes can
come from
halides via
E2.
Carbenes, :CH2
Preparation of simple carbenes
1.
carbene
2.
Mechanism of the a elimination.
Reactions of Carbenes, :CH2 (not for
synthesis)
Addition to double
bond.
Insertion into C-H bond
Formation of ylide (later)
liquid
Simmons Smith Reaction (for synthesis,
addition to alkenes to yield cyclopropanes)
CH2I2
+ Zn(Cu)

ICH2ZnI
Carbenoid, properties
similar to carbenes.
Electronic Structure
Electrons paired, singlet
Triplet and Singlet Methylene
Dominant form
in solution
Gas phase
CH2N2
singlet carbene
triplet carbene
Rotation can
occur around this
bond.
pi electrons
CH2
+
stereospecific
addition
diradical
non-stereospecific