1. 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: THF 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.

2. Now a practical example. Want to do this transformation which uses the very basic acetylide anion: 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. Problem in the generation of the acetylide anion: ROH is stronger acid than terminal alkyne and reacts preferentially with the NaNH 2 ! Replace the H with C 2 H 5

3. 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.

4. Revisit Epoxides. Recall 2 Ways to Make Them Epoxide or oxirane Note the preservation of stereochemistry

5. 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. 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.

6. 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…

7. Variety of Products can be obtained by varying the nucleophile H 2 O/ NaOH 1.LiAlH 4 2.H 2 O 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

8. An Example of Synthetic Planning Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a useful pattern. 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

9. Synthetic Applications nucleophile Realize that the H 2 NCH 2 - was derived from nucleophile: CN Formation of ether from alcohols. N used as nucleophile twice.

10. 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.

11. Preparation of Epichlorohydrin Try to anticipate the products… Recall regioselectivity for opening the cyclic chloronium ion.

12. Example – Retrosynthesis Analysis A  blocker

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

14. Oxidation of Sulfides

15. Organometallic Compounds Chapter 15

16. 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 Acetylide anions: Enolate anions: Try to see what factors promote the formation of the negative charge on the carbon atoms: hybridization, resonance. Synthetic Thinking: This offers many opportunities provided you can work with the two carbon straight chain segment. or

17. We examine two types of organometallics: RMgX, a Grignard reagent, and RLi, an organolithium compound Preparation  +  -  + Solvated by ether, aprotic solvent

18. Basicity Recall that a carbanion, R 3 C: -, 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.

19. Reactivity patterns Recall the S N 2 reaction where the alkyl group, R, is part of the electrophile. 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. + -

20. 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.

21. 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.

22. Recall an earlier Example of Retrosynthesis Analysis A  blocker The Main Point: nucleophilic reactivity provided by oxygen or nitrogen. We are not forming new C-C bonds.

23. 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-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. Now a substituted oxirane… Note attack on less hindered carbon Newly formed bond

24. 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).

25. Gilman Reagent (Lithium diorganocopper Reagents) Gilman Preparation of Gilman Reagents

26. 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: Next step: 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 Alkyl (not 3 o ), vinylic nucleophile electrophile

27. Particularly useful, reaction with vinyl halides to make an alkene. Note that the stereochemistry of the alkene is retained. trans

28. 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.

29. Synthetic Analysis Newly formed bond. Note its position relative to the OH. Similar to Grignard analysis.

30. Example of Retrosynthetic Analysis Design a synthesis using oxiranes The oxirane ring could be on either side of the OH. Look at both possibilities. or On the right, located here. Open oxirane here. Nucleophile makes this bond. 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.

31. 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 (OCH 3 ) then C- C then OH. Use an epoxide. Epoxides can come from alkenes via peracids. Alkenes can come from halides via E2.

32. Carbenes, :CH 2 1. 2. carbene Preparation of simple carbenes Mechanism of the  elimination.

33. Reactions of Carbenes, :CH 2 (not for synthesis) Addition to double bond. Insertion into C-H bond Formation of ylide (later) liquid

34. 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.

35. Template for Reactions Why stereospecific, why from same side as OH group? Interaction with metal holds the carbenoid on the top side.

36. Electronic Structure Electrons paired, singlet

37. Triplet and Singlet Methylene Dominant form in solution Gas phase Rotation can occur around this bond.