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.