LMZ/CHEM109A/ Winter 2010

Chapter 10: Reactions of alcohols, amines, ethers, epoxides and sulfur-containing compounds I. Nucleophilic substitution reactions for the conversion of alcohols to other functional groups A. Introduction:

4. Reaction of alcohols (especially 1 or 2) with phosphorus halide (Sec. 11.8) R R PCl3, PBr3, or PCl5 (+ HOPX2 R' R' H X X= Br or Cl) OH H inversion for 1 and 2 C R' = H or alkyl or aryl (Note: For the synthesis of alkyl chloride, thionyl chloride generally gives better yields than PCl3 or PCl5.) Mechanism (for reaction with PBr3)?

B. Conversion of alcohol to alkyl halide (Reaction at C-O bond) (sec. 11.1): in-situ converting OH into good leaving groups 1. Conversion of alcohol to alkyl bromide by reaction with HBr (or NaBr, H2SO4) R* Br + H2O R* OH + HBr R* OH + HBr R* Br + H2O 1 S N SN2 inversion 3 racemic 1 mixture Mechanism?

e.g. 1

H C H3 C

OH PBr3 CH2CH3

C. Conversion of alcohols to tosylate (Reaction at O-H bond) (Sec. 10.3) 2. Conversion of alcohol to alkyl chloride by reaction with Lucas reagent (HCl, ZnCl2) ZnCl2 * ZnCl2 R* Cl + H2O R* OH + HCl R* OH + HCl R Cl + H2O 1 S N SN2 inversion 3 racemic 1 mixture Mechanism?
R R' H OH R' = H or alkyl or aryl R O R' Cl S CH3 H O O O S tosyl chloride (p-TosCl) O tosylate retension NEt or pyridine
3

CH3 + NEt3HCl (or pyridinum chloride)

e.g. 2 Me C H Et OH

O Cl S O

CH3 pyridine

D. Conversion of alcohol to other functional groups via halides or tosylates: Stereochemical consequences (sec/ 10.3)
R R' H OH PCl3or PBr3 R' R X + H2 O H inversion R CH3 R' (p-TosCl) H + HCl OTos retension Nu e.g. N3 SN2 R' Nu e.g. N3 SN 2 R' R H Nu

3. Reaction of alcohols (especially 1 or 2) with thionyl chloride (Sec. 11.9)

R R' H OH R' = H or alkyl or aryl SOCl2 R' R X H stereochemistry?? (+ SO2 + HCl)

inversion

double inversion : overall retention

O R Cl S R' H O O-H R Nu

Mechanism?

inversion H

retension + inversion : overall inversion

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II. Elimination and rearrangement reactions of alcohols 1. Acid catalyzed dehydration of alcohol to alkene (Sec. 10.4) (3>2>1)

III. Oxidation of alcohols, aldehydes, and thiols A. Oxidation of alcohols and aldehydes (Sec. 10.5)
a. Oxidation of 1 alcohols to aldehydes or carboxylic acids
OH

[O], oxidation H R

[O], oxidation H

R C

N H H CrO3Cl aldehyde 1 alcohol (CrO , pyridine, HCl) 3

mechanism?

pyridinium chlorochromate (PCC)

e.g. Na2Cr2O7, H2O, R OH ethanol carboxylic acid Or Jone's reagent (CrO3, H3O+, acetone) OR KMnO4, H2O

[O] e.g. Na2Cr2O7, H2O, ethanol, OR CrO3, H3O+, acetone, (OR KMnO4, H2O)

b. Oxidation of 2 alcohols to ketones

OH

[O], oxidation R' e.g. PCC, CH2Cl2 OR Na2Cr2O7, H2O, ethanol OR CrO3, H3O+, acetone R

R C

[O] R' no further oxidation

- carbocation rearrangement may occur

H 2 alcohol

ketone

c. 3 alcohols cannot be oxidized

OH

[O], oxidation R' NO REACTION

R C

R" 3 alcohol

- SN2 reaction competes with E2 dehydration

mechanism:

2. Dehydration by POCl3 IV. Amines as organic bases (sec. 10.6) - amino (NH2- or NR2-) is a very poor leaving group; - amines does not undergo elimination or substitution reactions on the C-N bond.

- as base

LMZ/CHEM109A/ Winter 2010

V. Nucleophilic substitution reactions of ethers (ROR) A. RO- is poor leaving groups similar to OH-: need acid activation - reaction proceeds with neither pure SN2 or SN1. - regioselectivity:

B. SN1 or SN2 mechanism (PCl3 or TsCl not working)

D. basic conditions:

- regioselectivity controlled by sterics - stereochemistry: SN2

VI. Epoxide (one kind of ether) ring opening (sec. 10.8) A. Due to ring strain, much more reactive than normal ethers VII. Crown ethers - help dissolve metal cations - Na+ --- [15]-crown-5 - K+ -----[18]-crown-6 - Li+ ----[12]-crown-4

B. under acidic conditions-- opened by halide, even H2O and ROH

LMZ/CHEM109A/ Winter 2010

IX. Thiols, sulfide (sec. 10.11)

B. Organolithium compounds: prepared in alkanes - strongly basic (pKa >40), can be nucleophile as well - C-Li bond: polarized covalent bond (not ionic bond)

A. naming thiols - as the principle functional group, alkane + thiol (similar to alcohol case)

- naming priority: OH>SH>NH2, when treated as substituent, use 'mercapto'

C. Organomagnesium compounds -- Grignard reagents (in ethereal solvent) - strongly basic, but less reactive than corresponding lithium compounds. - C-Mg bond: polarized covalent bond, not ionic bond.

B. naming sulfide: (similar to ether)

C. Strong nucleophiles due to high polarizability (softness)

D. Reactions:

X. Organometallic compounds (sec. 10.12) A. compare: