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 Sequence of Steps: not react with non aqueous acid and 1. Protect: ROH + Cl-SiR' 3 Et 3 N ROSiR' 3 bases or moderate aq. acids and bases.

2. Do work: 3. Deprotect: Alcohol group protected, now do desired reactions.

Bu 4 N + F ROSiR' 3 THF ROH + F-SiR' 3

Now a practical example. Want to do this transformation which uses the very basic acetylide anion: Replace the H with C 2 H 5 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 NaNH 2 .

R'Br NaNH 2 R R' H R :

Problem

in the generation of the acetylide anion:

ROH is stronger acid than terminal alkyne

and reacts preferentially with the NaNH 2 !

Solution: protect the OH (temporarily convert it to silyl ether).

Most acidic proton.

Protect, deactivate OH Perform desired reaction steps.

Remove protection Alcohol group restored!!

Revisit Epoxides.

Recall

2 Ways to Make Them

H peroxyacid RCO 3 H Note the preservation of stereochemistry H H H OH H H Cl 2 base H 2 O H + enantiomer H anti addition Cl chlorhydrin O Epoxide or oxirane

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 CH 3 OH H H O H CH 3 H 2 SO 4 HO H H H CH 3 Very similar to opening of cyclic bromonium ion.

Review that subject.

OCH 3 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 l

ess sterically hindered carbon is attacked

.

CH 3 O O H H OH H H H CH 3 H 3 CO H CH 3 A wide variety of synthetic uses can be made of this reaction…

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

Attack here H 2 O/ NaOH OH 1.

2.

LiAlH 4 H 2 O

An Example of Synthetic Planning

Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a

useful pattern.

O :Nu OH The epoxide ring has to have been located here 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 H 2 NCH 2 - 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… Cl 2 , high temp Cl Recall regioselectivity for opening the cyclic chloronium ion.

Cl 2 / H 2 O OH base Cl Cl ClH 2 C O

Sulfides

Preparation

Symmetric R-S-R Na 2 S + 2 RX  Unsymmetric R-S R’ NaSH + RX  R-S-R RSH RSH + base  RS + R’X  RS – R-S R’

S sulfide

Oxidation of Sulfides

H 2 O 2 or NaIO 4 O S sulfoxide NaIO 4 O S sulfone O

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  RCH 2 NH 2 Synthetic thinking: Disconnect + CN NH 2 Br Acetylide anions: strong base RC CH RC C: Synthetic Thinking: This offers many opportunities provided you can work with the two carbon straight chain segment.

Ph RX RC CR Ph Ph Ph Enolate anions: O O base O O RX or O O X OEt OEt OEt H H H R Try to see what factors promote the formation of the negative charge on the carbon atoms: hybridization, resonance.

X Ph Ph

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

Basicity

Recall that a carbanion, R 3 C: , 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 S N 2 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.

CH 3 O OH O H H H H H CH 3 H CH 3 H 3 CO 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-CH 2 -CH 2 -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 O CH 2 CH=CH 2 CH 2 =CH - CH 2 MgBr 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).

OH

Gilman Reagent (Lithium diorganocopper Reagents)

Li R-X Preparation of Gilman Reagents R-Li CuI R 2 CuLi Gilman

Reactions of Gilman Reagent

Coupling Reaction bonds..

Used to create new C – C Overall result. R X + R’-X    R – R’ Necessary details As before: R-X Li Next step: R 2 CuLi R'-X Restrictions on the process. Caution.

R group which goes into Gilman may be methyl, 1 o (best not 2 o or 3 o ), allylic,

vinylic

(unusual), aryl nucleophile R-Li CuI R - R' R 2 CuLi electrophile Alkyl (not 3 o ), vinylic

Particularly useful, reaction with vinyl halides to make an alkene.

trans Note that the stereochemistry of the alkene is retained.

Gilman and oxiranes

1. R 2 CuLi HO O 2. H 2 O, 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.

Similar to Grignard analysis.

Synthetic Analysis

1. R 2 CuLi HO O 2. H 2 O, 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 OH Nucleophile can come in on only one position of oxirane, on the C to which the OH should not be attached… OH Ph

On the left

, located here.

Open oxirane here.

Nucleophile makes this bond.

O OH or Ph On the right, located here. Open oxirane here. Nucleophile makes this bond.

(PhCH 2 ) 2 CuLi 2 synthetic routes available O LiCu(CH 2 CH 3 ) 2 Ph

O OCH 3

Synthesis Example

Carry out the following transformation in as many steps as needed.

Br O OCH 3 OH target O OCH 3 Br Remember oxidation of a secondary alcohol can produce a ketone.

Note pattern of a nucleophile (OCH 3 ) then C C then OH. Use an epoxide.

Epoxides can come from alkenes via peracids.

Alkenes can come from halides via E2.

Carbenes, :CH

2 Preparation of simple carbenes 1.

2.

Mechanism of the a elimination.

carbene

Reactions of Carbenes, :CH 2 (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) CH 2 I 2 + Zn(Cu)  ICH 2 ZnI Carbenoid, properties similar to carbenes.

Electronic Structure

Electrons paired, singlet

CH 2 N 2

Triplet and Singlet Methylene

Dominant form in solution Gas phase singlet carbene triplet carbene Rotation can occur around this bond.

pi electrons stereospecific addition CH 2 diradical + non-stereospecific