FIVE METHODS OF PREPARING ALCOHOLS

1. FIVE METHODS OF PREPARING ALCOHOLS

2. 5 METHODS OF PREPARING ALCOHOLS 1. Hydroxide ions (OH-) replace halogens in unhindered alkyl halides (Me° and 1°) via an SN2 reaction. The product is an alcohol.

3. 5 METHODS OF PREPARING ALCOHOLS The Nu:- removes an H+ from a b-carbon & the halogen leaves forming an alkene. • But when a hindered alkyl halide (2° or 3°) is treated with a strong base such as NaOH, dehydrohalogenation occurs producing an alkene – an E2 reaction. Aryl and vinyl halides do not react via SN1, SN2, E1or E2 reactions.

4. 5 METHODS OF PREPARING ALCOHOLS • 2. Alkenes are hydrated by heating with dilute aq. H2SO4 (catalyst). • The E+ (H+) adds to the less substituted sp2 C Nu:- in the p-bond forming the more stable C+ intermediate. The C+ may rearrange. • Water, a weak Nu:-, adds to the C+. • The oxonium ion is deprotonated (loses H+) by H2O or HSO4-, regenerating the catalyst and forming the Markovnikov alcohol (1-methylcyclohexanol in this example).

5. 5 METHODS OF PREPARING ALCOHOLS • Recall that oxymercuration, demercuration also produces the Markovnikov alcohol, but without C+ rearrangement. • The Hg ion adds first and forms a bridge to the C+, stabilizing it and preventing rearrangement.

6. 5 METHODS OF PREPARING ALCOHOLS • Recall that hydroboration, oxidation produces the anti-Markovnikov alcohol without C+ rearrangement.

7. 5 METHODS OF PREPARING ALCOHOLS Carbonyl compounds are reduced to alcohols. DIGRESSION: Order of reactivity of carbonyls. acid chloride acid anhydride aldehyde ketone ester carboxylicacid amide nitrile carboxylate most reactive least reactive

8. 5 METHODS OF PREPARING ALCOHOLS Sodium borohydride (NaBH4),lithium aluminum hydride (LiAlH4) and Grignards (RMgX) reduce many carbonyls to alcohols. acid chloride acid anhydride aldehyde ketone ester carboxylicacid amide nitrile carboxylate Reduced to alcohols by NaBH4 Reduced to alcohols by Grignards (RMgX) LIAlH4 is a powerful Nu:- and is explosive water. NaBH4 is a good Nu:- and is safe to use in water. Grignards (RMgX) are very strong bases and are destroyed by water and other weak acids. LiAlH4 reduces all carbonyls.

9. 5 METHODS OF PREPARING ALCOHOLS Prep. of NaBH4 & LiAlH4 are shown. These reactions are reversible.

10. 5 METHODS OF PREPARING ALCOHOLS • NaBH4 and LiAlH4 dissociate in the presence of carbonyl compounds producing hydride (H:-) ion, an excellent Nu:-. • Grignards (RMgX) dissociate in the presence of carbonyl compounds producing an alkide (R:-) ion, an excellent Nu:- 3. Reduction of aldehydes with NaBH4 or LiAlH4 producing 1° alcohols. Mechanism:

11. 5 METHODS OF PREPARING ALCOHOLS 3. Reduction of ketones with NaBH4 or LiAlH4 producing 2° alcohols. Mechanism: • Although both NaBH4 and LiAlH4 are effective, NaBH4 is normally used as it is safer. LiAlH4 is reserved for less reactive carbonyl compounds such as esters and carboxylic acids.

12. 5 METHODS OF PREPARING ALCOHOLS Draw and name the products of the following hydride reduction reactions. Hydrides do not react with alkenes. Both are nucleophiles.

13. 5 METHODS OF PREPARING ALCOHOLS 4. Reduction of esters (and carboxylic acids) with LiAlH4 producing 1° alcohols. NaBH4 is not strong enough. LiAlH4 must be used for these carbonyls. Mechanism:

14. 5 METHODS OF PREPARING ALCOHOLS • Note that aldehydes and ketones have no leaving groups. The alkoxide intermediate will not lose a H:- or R:- so NaBH4 only adds once. Esters, however, lose an alkoxide (OR-). • OR- (pKb = -2) , like OH- (pKb = -1.74), is a poor leaving group but LiAlH4 is powerful enough to displace it from the carbonyl. Two moles of LiAlH4 are required for reduction of esters. Draw and name the product of hydride reduction of the ester,methyl benzoate.

15. 5 METHODS OF PREPARING ALCOHOLS Carboxylic acids react with 3 moles LiAlH4 producing 1° alcohols. MECHANISM:

16. 5 METHODS OF PREPARING ALCOHOLS LiAlH4 is reactive enough to reduce even carboxylates, the weakest electrophile of the carbonyl compounds. Draw and name the product of the following hydride reductions.

17. 5 METHODS OF PREPARING ALCOHOLS 5. Reduction of carbonyls with Grignards (RMgX) producing alcohols. • Grignards (RMgX) dissociate in the presence of carbonyl compounds producing an alkide (R:-) ion, an excellent Nu:- • Grignards are prepared by mixing finely divided Mg and an alkyl halide in ether solvent. Mg is inserted between the alkyl group and the halogen. R-X + Mg  R-MgX where R = 1º, 2, or 3 alkyl, aryl, or vinylic where X = Cl, Br, or I

18. 5 METHODS OF PREPARING ALCOHOLS • Grignards react with formaldehyde, CH2=O, to give 1 alcohols. They react with higher aldehydes to give 2 alcohols and esters to give 3 alcohols.

19. 5 METHODS OF PREPARING ALCOHOLS • Grignards react with ketones and esters to give 3 alcohols.

20. 5 METHODS OF PREPARING ALCOHOLS • Unlike LiAlH4, Grignards do not reduce carboxylic acids to alcohols. • Grignards (strong bases) neutralize carboxylic acids to carboxylates, but, unlike LiAlH4, Grignards are not strong enough nucleophiles to react with carboxylates (weak electrophiles) .

21. 5 METHODS OF PREPARING ALCOHOLS • Grignards are destroyed (protonated) by even very weakly acidic functional groups. • All the groups listed below have a H acidic enough to protonate the highly basic Grignard reagents. Assuming alkyl amines (pKa =35) to be the weakest acid that would protonate a Grignard, calculate the approximate pKb of a Grignard. pKeq = pKa + pKb – 14 0 = 35 + pKb -14 pKb = 14 – 35 = -21

22. 5 METHODS OF PREPARING ALCOHOLS Draw products formed when methyl magnesium bromide (CH3MgBr) reacts with the following.

23. 5 METHODS OF PREPARING ALCOHOLS The following product was formed using Grignards. Draw all possible sets of reagents.

24. Do the practice problems in your purchased notes!