Chap 9: Alcohols, Ethers

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Chap 9 Alcohols, Ethers Epoxides
IntroductionStructure and Bonding

• Alcohols contain a hydroxy group (OH) bonded to
  an sp3 hybridized carbon.

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Alcohols, Ethers and Epoxides
IntroductionStructure and Bonding

• Compounds having a hydroxy group on a sp2
  hybridized carbonenols and phenolsundergo
  different reactions than alcohols.

• Ethers have two alkyl groups bonded to an oxygen
  atom.

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Alcohols, Ethers and Epoxides
IntroductionStructure and Bonding

• Epoxides are ethers having the oxygen atom in a
  three-membered ring. Epoxides are also called
  oxiranes.

• The COC bond angle for an epoxide must be 60,
  a considerable deviation from the tetrahedral
  bond angle of 109.5. Thus, epoxides have angle
  strain, making them more reactive than other
  ethers.

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Alcohols, Ethers and Epoxides
Physical Properties

• Alcohols, ethers and epoxides exhibit
  dipole-dipole interactions because they have a
  bent structure with two polar bonds.
• Alcohols are capable of intermolecular (and
  intramolecular eg protiens DNA RNA) hydrogen
  bonding. So, alcohols are more polar than ethers
  and epoxides.

• Steric factors affect hydrogen bonding.

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Alcohols, Ethers and Epoxides
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Alcohols, Ethers and Epoxides
Preparation of Alcohols, Ethers, and Epoxides

• Alcohols and ethers are common products of
  nucleophilic substitution.

• Williamson ether synthesis.

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Alcohols, Ethers and Epoxides
Preparation of Alcohols, Ethers, and Epoxides

• Unsymmetrical ethers can be synthesized in two
  different ways usually one approach is preferred.

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Preparation of Alcohols, Ethers, and Epoxides

• An alkoxide salt is needed to make an ether.
• Alkoxides are prepared from alcohols by a
  BrØnsted-Lowry acidbase reaction.

• NaH is an especially good base for this because
  the by-product of the reaction, H2, is a gas that
  just bubbles out of the reaction mixture.

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Preparation of Alcohols, Ethers, and Epoxides

• Organic compounds that contain both a hydroxy
  group and a halogen atom on adjacent carbons are
  called halohydrins.
• In halohydrins, an intramolecular version of the
  Williamson ether synthesis can occur to form
  epoxides.

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Reactions of Alcohols

• The OH group in alcohols is a very poor leaving
  group.

• For an alcohol to undergo nucleophilic
  substitution, the OH must be converted into a
  better leaving group. Example an acid can
  convert the OH into H2O, giving a good leaving
  group.

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Reactions of AlcoholsDehydration

• Dehydration, like dehydrohalogenation, is a ?
  elimination reaction in which the elements of OH
  and H are removed from the ? and ? carbon atoms
  to form water.

• Dehydration is usually carried out using H2SO4
  and other strong acids, or phosphorus oxychloride
  (POCl3) in the presence of an amine base.

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Reactions of AlcoholsDehydration

• Common acids used for alcohol dehydration are
  H2SO4 or p-toluenesulfonic acid (TsOH) tosyl.

• More substituted alcohols dehydrate more easily

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Reactions of AlcoholsDehydration

• When an alcohol has two or three ? carbons,
  dehydration is regioselective and follows the
  Zaitsev rule.
• The more substituted alkene is the major product
  when a mixture of constitutional isomers is
  possible.

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Reactions of AlcoholsDehydration

• Secondary and 3 alcohols react by an E1
  mechanism, whereas 1 alcohols react by an E2
  mechanism.

Example as a review of E1 and E2 mechanisms
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Reactions of AlcoholsDehydration

• The E1 dehydration of 20 and 30 alcohols with
  acid gives elimination products without
  significant amounts of by-products from an SN1
  reaction.
• Elimination takes place because the reaction
  mixture contains no good nucleophile to react
  with the intermediate carbocation, so little/no
  competing SN1 reaction.
• So, E1 dehydration of alcohols is much more
  synthetically useful than the E1
  dehydrohalogenation of alkyl halides.

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Reactions of AlcoholsDehydration

• Since 1 carbocations are highly unstable, their
  dehydration cannot occur by an E1 mechanism
  involving a carbocation intermediate. Therefore,
  1 alcohols undergo dehydration following an E2
  mechanism.

Example as a review of E2 mechanism
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Alcohols, Ethers and Epoxides
Reactions of AlcoholsDehydration

• Entropy favors product formation in dehydration,
  but enthalpy does not, since the ? bonds broken
  in the reactant are stronger than the ? and ?
  bonds formed in the products (broken formed).
  So, distill away product as it is formed.

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Carbocation Rearrangementshydride shifts

• When carbocations are intermediates, a less
  stable carbocation can sometimes be converted
  into a more stable carbocation by a shift of a
  hydrogen or an alkyl group (a rearrangement).

Example of a shift from a secondary alcohol to
tertiary carbocat
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Dehydration of Alcohols Using POCl3 and Pyridine

• Many organic compounds decompose when exposed to
  a strong acid, so... phosphorus oxychloride
  (POCl3) and pyridine (an amine base) can be used
  in place of H2SO4 or TsOH.

• POCl3 converts a poor leaving group (OH) into a
  good leaving group.
• Dehydration then follows an E2 mechanism.

Mechanism
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Conversion of Alcohols to Alkyl Halides with HX

• Substitution reactions do not occur with alcohols
  unless OH is converted into a good leaving group.

• The reaction of alcohols with HX (X Cl, Br, I)
  is a good method to prepare 1, 2, and 3 alkyl
  halides.

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Conversion of Alcohols to Alkyl Halides with HX

• This order of reactivity can be rationalized by
  considering the reaction mechanisms involved. The
  mechanism depends on the structure of the R group.

Mechanism
So primary give inversion, tertiary racemic mix
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Conversion of Alcohols to Alkyl Halides with HX

• The reactivity of hydrogen halides increases with
  increasing acidity.

• Because Cl is a poorer nucleophile than Br or
  I, the reaction of 10 alcohols with HCl occurs
  only when an additional Lewis acid catalyst.

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Conversion of 1o nad 2o Alcohols to Alkyl Halides
with SOCl2 and PBr3

• SOCl2 (thionyl chloride) converts alcohols into
  alkyl chlorides.
• PBr3 (phosphorus tribromide) converts alcohols
  into alkyl bromides.
• Both reagents convert OH into a good leaving
  group in situ (directly in the reaction mixture)
  AND provide the nucleophile to displace the
  leaving group!

Mechanism, similar for the two reagents
Pyridine is a common solvent that is converted
into pyridinium chloride, but its not
green. Need a nitrogen containing solvent
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Alcohols Tosylates

• Tosylate is a good leaving group its conjugate
  acid, p-toluenesulfonic acid (CH3C6H4SO3H, TsOH)
  is a strong acid with pKa -7.

Tosyl formation though retention of
configuration, then mechanism can go either way
inversion or racemic
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Alcohols Tosylates

• Tosylate is a good leaving group, so both
  nucleophilic substitution and ? elimination can
  occur.
• Best to treat with either a strong nucleophile or
  bases, so get SN2 or E2.

• SN2 mechanism gives inversion of configuration
  when chiral.

Mechanism compare methoxide with t-butoxide
nucleophiles on ROTs
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Summary alcohols
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Reaction of Ethers with Strong Acid not
synthetically very usefuldont focus on this
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Reactions of Epoxides

• Epoxides contain a strained three-membered ring
  with two polar bonds.
• Nucleophilic attack opens the strained
  three-membered ring, making it a favorable
  process even with a poor leaving group.

Mechanism to open, create chiral centers, then
convert OH to Lv grp if want
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Reactions of Epoxides which side do I attack?
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Reactions of Epoxides Stereochemistry of
opening (acid or base catalyzed)
Nucleophilic attack of OCH3 occurs from the
backside at either CO bond, because both ends
are similarly substituted.
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Reactions of Epoxides acid cat formation of 1,2
diols NOT enant pure though!
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Reactions of Epoxides
Balance with sterics too
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Reactions of Epoxides Ring opening acidic or
basic

• Ring opening of an epoxide with either a strong
  nucleophile or an acid HZ is regioselective
  because one constitutional isomer is the major or
  exclusive product.
• The site of selectivity of these two reactions is
  opposite from another.