Ethers, Sulfides, Epoxides

1. Ethers, Sulfides, Epoxides

2. Variety of ethers, ROR Aprotic solvent

3. Reactions of ethers • Ethers are inert to (do not react with) • Common oxidizing reagents (dichromate, permanganate) • Strong bases • Weak acids. But see below. HX protonates ROH, set-up leaving group followed by SN2 (10) or SN1 (20 or 30). Ethers do react with conc. HBr and HI. Recall how HX reacted with ROH. Look at this reaction and attempt to predict the mechanism… Regard as leaving group. Compare to OH, needs protonation. Expectations for mechanism Protonation of oxygen to establish leaving group For 1o alcohols: attack of halide, SN2 For 2o, 3o: formation of carbocation, SN1 • Characterize this reaction: • Fragmentation • Substitution

4. Mechanism This alcohol will now be protonated and reacted with halide ion to yield RX. Inversion will occur. Inversion of this R group This alcohol is protonated, becomes carbocation and reacts with halide. Loss of chirality at reacting carbon. Possible rearrangement.

5. Properties of ethers Aprotic Solvent, cannot supply the H in H-bonding, no ether to ether hydrogen bonding Ethers are polar and have boiling points close to the alkanes. propane (bp: -42) dimethyl ether (-24) ethanol (78)

6. Hydrogen Bonding Requirements of Hydrogen Bonding: Need both H acceptor and donor. protic Ethers are not protic, no ether to ether H bonding However, ethers can function as H acceptors and can engage in H bonding with protic compounds. Small ethers have appreciable water solubility.

7. Synthesis of ethers Williamson ether synthesis RO- + R’X  ROR’ nucleophile electrophile • Characteristics • RO-, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered) and a strong base. Both SN2 (desired) and E2 (undesired side product) can occur. • Choose nucleophile and electrophile carefully. Maximize SN2 and minimize E2 reaction by choosing the R’X to have least substituted carbon undergoing substitution (electrophile). Methyl best, then primary, secondary marginal, tertiary never (get E2 instead). • Stereochemistry: the reacting carbon in R’, the electrophile which undergoes substitution, experiences inversion. The alkoxide undergoes no change of configuration.

8. Analysis (devise reactants and be mindful of stereochemistry) • Use Williamson ether synthesis. • Which part should be the nucleophile? • Which is the electrophile, the compound undergoing substitution? • Electrophile should ideally be 1o. Maximizes subsitution and minimizes elimination. Provide a synthesis starting with alcohols. We can set it up in two different ways: Nucleophile Electrophile, RX undergoing substitution Remember: the electrophile (RX) will experience inversion. Must allow for that! 1o 1o or Nucleophile Electrophile, RX undergoing substitution 2o 2o

9. Electrophile (RX) SN2 1o Note allowance for inversion Nucleophile 2o Preferably use tosylate as the leaving group, X. Thus…. TsCl { retention SN2 Done! inversion K retention

10. Acid catalyzed dehydration of alcohols to yield ethers. • Key ideas: • Acid will protonate alcohol, setting up good leaving group. • A second alcohol molecule can act as a nucleophile. The nucleophile (ROH) is weak but the leaving group (ROH) is good. • Mechanism is totally as expected: • Protonation of alcohol (setting up good leaving group) • For 2o and 3o ionization to yield a carbocation with alkene formation as side product. Attack of nucleophile (second alcohol molecule) on carbocation. • For 1o attack of nucleophile (second alcohol molecule) on the protonated alcohol.

11. Mechanism For primary alcohols. For secondary or tertiary alcohols. SN1 substitution H-O-H leaves, R-O-H attached. E1 elimination

12. Use of Mechanistic Principles to Predict Products protonate Have set-up leaving group which would yield secondary carbocation. Check for rearrangements. 1,2 shift of H. None further. Carbocation reacts with nucleophile, another alcohol. deprotonate

13. Acid catalyzed addition of alcohol to alkene Recall addition of water to an alkene (hydration). Acid catalyzed, yielded Markovnikov orientation. Using an alcohol instead of water is really the same thing!! Characteristics Markovnikov Alcohol should be primary to avoid carbocations being formed from the alcohol. Expect mechanism to be protonation of alkene to yield more stable carbocation followed by reaction with the weakly nucleophilic alcohol. Not presented.

14. 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

15. 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!

16. 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!!

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

18. 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.

19. 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…

20. 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 • LiAlH4 • H2O

21. 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

22. Synthetic Applications nucleophile Realize that the H2NCH2- was derived from nucleophile: CN N used as nucleophile twice. Formation of ether from alcohols.

23. 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.

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

25. Sulfides Preparation 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’

26. Oxidation of Sulfides