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 S N 2 reaction. The product is an alcohol.

3 5 METHODS OF PREPARING ALCOHOLS 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 S N 1, S N 2, E1or E2 reactions. The Nu: - removes an H + from a  -carbon & the halogen leaves forming an alkene.

4 2. Alkenes are hydrated by heating with dilute aq. H 2 SO 4 (catalyst). 5 METHODS OF PREPARING ALCOHOLS  The E + (H + ) adds to the less substituted sp 2 C Nu: - in the  -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 H 2 O or HSO 4 -, 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. most reactive acid chloride acid anhydride aldehyde ketone ester carboxylic acid amide nitrile carboxylate least reactive

8 5 METHODS OF PREPARING ALCOHOLS Sodium borohydride (NaBH 4 ),lithium aluminum hydride (LiAlH 4 ) and Grignards (RMgX) reduce many carbonyls to alcohols. acid chloride acid anhydride aldehyde ketone ester carboxylic acid amide nitrile carboxylate Reduced to alcohols by Grignards (RMgX) LiAlH 4 reduces all carbonyls. NaBH 4 is a good Nu: - and is safe to use in water. LIAlH 4 is a powerful Nu: - and is explosive water. Reduced to alcohols by NaBH 4 Grignards (RMgX) are very strong bases and are destroyed by water and other weak acids.

9 5 METHODS OF PREPARING ALCOHOLS Prep. of NaBH 4 & LiAlH 4 are shown. These reactions are reversible.

10 5 METHODS OF PREPARING ALCOHOLS  NaBH 4 and LiAlH 4 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 NaBH 4 or LiAlH 4 producing 1° alcohols. Mechanism:

11 5 METHODS OF PREPARING ALCOHOLS 3. Reduction of ketones with NaBH 4 or LiAlH 4 producing 2° alcohols. Mechanism:  Although both NaBH 4 and LiAlH 4 are effective, NaBH 4 is normally used as it is safer. LiAlH 4 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 LiAlH 4 producing 1° alcohols. NaBH 4 is not strong enough. LiAlH 4 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 NaBH 4 only adds once. Esters, however, lose an alkoxide (OR - ).  OR - (pKb = -2), like OH - (pKb = -1.74), is a poor leaving group but LiAlH 4 is powerful enough to displace it from the carbonyl. Two moles of LiAlH 4 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 LiAlH 4 producing 1° alcohols. MECHANISM:

16 5 METHODS OF PREPARING ALCOHOLS LiAlH 4 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, CH 2 =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 LiAlH 4, Grignards do not reduce carboxylic acids to alcohols.  Grignards (strong bases) neutralize carboxylic acids to carboxylates, but, unlike LiAlH 4, 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 – 140 = 35 + pKb -14 pKb = 14 – 35 = -21

22 5 METHODS OF PREPARING ALCOHOLS Draw products formed when methyl magnesium bromide (CH 3 MgBr) 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!