important synthetic technique: protecting groups. using silyl ethers to protect alcohols protecting...
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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.
Sequence of Steps:
ROH + Cl-SiR'3
Et3NROSiR'3
Alcohol group protected, now do desired reactions.
ROSiR'3
Bu4N+ F-
ROH + F-SiR'3THF
1. Protect:
2. Do work:
3. Deprotect:
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.
Now a practical example. Want to do this transformation which uses the very basic acetylide anion:
R H
NaNH2R'Br
R R'R :
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!
Replace the H with C2H5
Protect, deactivate OH
Perform desired reaction steps.
Remove protection
Solution: protect the OH (temporarily convert it to silyl ether).
Alcohol group restored!!
Most acidic proton.
Revisit Epoxides. Recall 2 Ways to Make Them
peroxyacidRCO3H
O
Cl2
H2O
OH
Cl
base
anti addition
+ enantiomer
chlorhydrin
H
H
H
H
H
H
H
H
Epoxide or oxirane
Note the preservation of stereochemistry
Use of Epoxide Ring, Opening in Acid
O
CH3
H
HH
H
CH3OH
CH3H
OCH3
HO
HH
H2SO4
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.
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.
Very similar to opening of cyclic bromonium ion. Review that subject.
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.
O
CH3
HH
H
CH3O-
CH3
H
OH
H3CO
HH
A wide variety of synthetic uses can be made of this reaction…
Variety of Products can be obtained by varying the nucleophile
H2O/ NaOH
1. LiAlH4
2. H2O
OH
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
Attack here
An Example of Synthetic PlanningReactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a useful pattern.
O:Nu OH
Nu
The pattern to be recognized in the
product is –C(-OH) – C-Nu
The epoxide ring has to have
been located here
This bond was created by the
nucleophile
Synthetic Applicationsnucleophile
Realize that the H2NCH2- was derived from nucleophile: CN
Formation of ether from alcohols.
N used as nucleophile twice.
Epichlorohyrin and Synthetic Planning, same as before but now use two nucleophiles
Observe the pattern in the productNu - C – C(OH) – C - Nu. When you observethis pattern it suggests the use of epichlorohydrin.
Both of these bonds will be formed by the incoming nucleophiles.
Preparation of Epichlorohydrin
Cl2, high temp
Cl
Cl2 / H2O
Cl
OH
Cl
base
Try to anticipate the products…
Recall regioselectivity for opening the cyclic
chloronium ion.
O
ClH2C
Sulfides
Symmetric R-S-R
Na2S + 2 RX R-S-R
Unsymmetric R-S-R’
NaSH + RX RSH
RSH + base RS –
RS- + R’X R-S-R’
Preparation
Oxidation of Sulfides
S
sulfide
S
O
sulfoxide
S
O
O
sulfone
H2O2 or NaIO4 NaIO4
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
Acetylide anions:
Enolate anions:
OEt
O O base
OEt
O O
H HH
RX
OEt
O O
R
RC CH
strong base
RC C:
RX
RC CR
Try to see what factors promote the formation of the negative charge on the carbon atoms: hybridization, resonance.
Synthetic thinking: Disconnect
NH2+ CN-
Br
Synthetic Thinking: This offers many opportunities provided you can work with the two carbon straight chain segment. Ph
Ph
Ph
Ph
X
Ph
Ph
Xor
We examine two types of organometallics: RMgX, a Grignard reagent, and RLi, an organolithium compound
Preparation
+ -
- +
Solvated by ether, aprotic solvent
BasicityRecall that a carbanion, R3C:-, is a very strong base.
So also Grignards and alkyl lithiums.
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.
Ethane, a gas.
Reactivity patternsRecall the SN2 reaction where the alkyl group, R, is part of the electrophile.
Nu:- + R-X Nu - R + X-
Electrophile
Nucleophile
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- +
Nucleophile
Electrophile
Electrostatic potential maps.
+ -
Recall Reactions of Oxiranes with Nucleophiles
Recall opening of oxirane with a strong, basic nucleophile.
O
CH3
HH
H
CH3O-
CH3
H
OH
H3CO
HH
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 Applicationsnucleophile
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
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.
Now a substituted oxirane…
Note attack on less hindered carbon
Newly formed bond
Newly formed bond
Synthesis Example
OH
CH2CH=CH2
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).
O
CH2=CH - CH2MgBr
OH
Gilman Reagent (Lithium diorganocopper Reagents)
R-X
LiR-Li
CuIR2CuLi
GilmanPreparation of Gilman Reagents
Reactions of Gilman ReagentCoupling Reaction Used to create new C – C bonds..
Overall result. R-X + R’-X R – R’
Necessary details
R-X
LiR-Li
CuIR2CuLiAs before:
Next step: R2CuLiR'-X
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
electrophile
Particularly useful, reaction with vinyl halides to make an alkene.
Note that the stereochemistry of the alkene is retained.
trans
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.
O1. R2CuLi HO
R
2. H2O, HCl
Synthetic Analysis
O1. R2CuLi HO
R
2. H2O, HCl
Newly formed bond. Note its position
relative to the OH.
Similar to Grignard analysis.
Example of Retrosynthetic Analysis
Ph
OH
Design a synthesis using oxiranesThe oxirane ring could be on either side of the OH. Look at both possibilities.
Ph
OH
orPh
OH
O
(PhCH2)2CuLi
On the right, located here. Open oxirane here. Nucleophile makes this bond.
Ph
O
LiCu(CH2CH3)2
2 synthetic routes available
Nucleophile can come in on only one position of oxirane, on the C to which the OH should not be attached…
On the left, located here.Open oxirane here.Nucleophile makes this bond.
Synthesis ExampleCarry out the following transformation in as many steps as needed.
Br O
OCH3
O
OCH3
OH
OCH3
O
Brtarget
Remember oxidation of a secondary alcohol can produce a ketone.
Note pattern of a nucleophile (OCH3) then C-C then OH. Use an epoxide.
Epoxides can come from alkenes via peracids.
Alkenes can come from halides via E2.
Carbenes, :CH2
1.
2.
carbene
Preparation of simple carbenes
Mechanism of the 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
CH2N2
singlet carbene
stereospecificaddition
pi electrons
triplet carbene
CH2
diradical
+
non-stereospecific
Dominant form in solution
Gas phase
Rotation can occur around this
bond.