Important Synthetic Technique: protecting groups. Using Silyl ethers to Protect Alcohols

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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 render the OH inert.
Silyl ether. Does not react with non aqueous acid
and bases or moderate aq. acids and bases.
Sequence of Steps
1. Protect
2. Do work
3. Deprotect
THF
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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.
Problem in the generation of the acetylide anion
ROH is stronger acid than terminal alkyne and
reacts preferentially with the NaNH2!
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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!!
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Revisit Epoxides. Recall 2 Ways to Make Them
Note the preservation of stereochemistry
Epoxide or oxirane
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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.
Very similar to opening of cyclic bromonium ion.
Review that subject.
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.
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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.
A wide variety of synthetic uses can be made of
this reaction
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Variety of Products can be obtained by varying
the nucleophile
Attack here
H2O/ NaOH
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

1. LiAlH4
2. H2O

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An Example of Synthetic Planning
Reactions of a nucleophile (basic) with an
epoxide/oxirane ring reliably follow a useful
pattern.
The epoxide ring has to have been located here
This bond was created by the nucleophile
The pattern to be recognized in the product is
C(-OH) C-Nu
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Synthetic Applications
nucleophile
Realize that the H2NCH2- was derived from
nucleophile CN
N used as nucleophile twice.
Formation of ether from alcohols.
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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.
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Preparation of Epichlorohydrin
Try to anticipate the products
Recall regioselectivity for opening the cyclic
chloronium ion.
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Example Retrosynthesis Analysis
A b blocker
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Sulfides
Preparation
Symmetric R-S-R Na2S 2 RX ? R-S-R
Unsymmetric R-S-R NaSH RX ? RSH
RSH base ? RS RS- RX ?
R-S-R
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Oxidation of Sulfides
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Organometallic Compounds

• Chapter 15

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Carbon Nucleophiles Critical in making larger
organic molecules. Review some of the ones that
we have talked about.
Cyanide ion CN- RX ? RCN ? RCH2NH2
Acetylide anions
Synthetic Thinking This offers many
opportunities provided you can work with the two
carbon straight chain segment.
Enolate anions
or
Try to see what factors promote the formation of
the negative charge on the carbon atoms
hybridization, resonance.
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We examine two types of organometallics RMgX, a
Grignard reagent, and RLi, an organolithium
compound
Preparation
d -
d
d -
d
Solvated by ether, aprotic solvent
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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.
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Reactivity patterns
Recall the SN2 reaction where the alkyl group, R,
is part of the electrophile.
Nucleophile
Nucleophile
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.
-

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Recall Reactions of Oxiranes with Nucleophiles
Recall opening of oxirane with a strong, basic
nucleophile.
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.
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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.
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Recall an earlier Example of Retrosynthesis
Analysis
A b blocker
The Main Point nucleophilic reactivity provided
by oxygen or nitrogen. We are not forming new C-C
bonds.
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A Grignard has a reactive, negative carbon. Now
examine reaction of Grignard and oxirane ring.
Newly formed bond
Net results 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
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Synthesis Example
Retrosynthesize the following
Recall reaction of a nucleophile with an
(oxirane) epoxide to give a HO-C-C-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).
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Gilman Reagent (Lithium diorganocopper Reagents)
Gilman
Preparation of Gilman Reagents
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Reactions of Gilman Reagent
Coupling Reaction Used to create new C C bonds..
Overall result. R-X R-X ? ? ? R R
Necessary details
As before
electrophile
Next step
Restrictions on the process. Caution.
Alkyl (not 3o), vinylic
R group which goes into Gilman may be methyl, 1o
(best not 2o or 3o), allylic, vinylic (unusual),
aryl
nucleophile
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Particularly useful, reaction with vinyl halides
to make an alkene.
trans
Note that the stereochemistry of the alkene is
retained.
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Gilman and oxiranes
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.
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Synthetic Analysis
Similar to Grignard analysis.
Newly formed bond. Note its position relative to
the OH.
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Example of Retrosynthetic Analysis
Design a synthesis using oxiranes
Nucleophile can come in on only one position of
oxirane, on the C to which the OH should not be
attached
The oxirane ring could be on either side of the
OH. Look at both possibilities.
or
On the left, located here.
On the right, located here. Open oxirane here.
Nucleophile makes this bond.
Open oxirane here.
Nucleophile makes this bond.
2 synthetic routes available
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Synthesis Example
Carry out the following transformation in as many
steps as needed.
target
Remember oxidation of a secondary alcohol can
produce a ketone.
Note pattern of a nucleophile (OCH3) then C-C
then OH. Use an epoxide.
Alkenes can come from halides via E2.
Epoxides can come from alkenes via peracids.
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Carbenes, CH2
Preparation of simple carbenes
1.
carbene
2.
Mechanism of the a elimination.
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Reactions of Carbenes, CH2 (not for synthesis)
Addition to double bond.
liquid
Insertion into C-H bond
Formation of ylide (later)
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Simmons Smith Reaction (for synthesis, addition
to alkenes to yield cyclopropanes)
CH2I2 Zn(Cu) ? ICH2ZnI
Carbenoid, properties similar to carbenes.
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Template for Reactions
Why stereospecific, why from same side as OH
group?
Interaction with metal holds the carbenoid on the
top side.
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Electronic Structure
Electrons paired, singlet
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Triplet and Singlet Methylene
Dominant form in solution
Gas phase
Rotation can occur around this bond.