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CHAPTER 9: ALCOHOLS AND ETHERS

NOMENCLATURE AND EXAMPLES

ALCOHOLS

COMMON ALCOHOLS

Ethanol Methanol Isopropanol Glycerin

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NAMING ALCOHOLS

1.! Number the parent chain so the –OH group is the lowest number possible. Ending is –ol.

2.! With cyclic alcohols, the –OH group is understood to be position #1 (does not need to be indicated).

ETHERS

COMMON ETHERS Anesthetics

Diethyl Ether first to produce deep anesthesia in 1846

Enflurane Anesthetic in 1970’s

and 80’s

Sevoflurane Current anesthetic

Solvents

Diethyl ether Tetrahydrofuran (THF) 1,4-dioxane (Dioxane) Daughter was sedated with sevoflurane in 2012

OO

O

O

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NAMING ETHERS

1)! SIMPLE ETHERS

Name each alkyl group alphabetically, and add “ether” as a separate word.

MTBE (used as a gasoline anti-knock additive starting in 2003) gives water an unpleasant taste at very low concentrations. It is not carcinogenic, and can be degraded by bacteria. However, it is partially banned in US.

“MTBE is the 2nd most frequently detected VOC in domestic and public wells despite its relatively short production and use history.”1 However, most concentrations are much lower than EPA recommendations.

2)! MORE COMPLEX ETHERS

Name the simpler alkyl group as an “alkoxy” group, and consider it a substituent. Name the compound in a regular manner (ether is not the parent group).

1 https://water.usgs.gov/nawqa/vocs/national_assessment/report/chapter5.html (Aug, 2017)

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SYNTHESIS OF ALCOHOLS AND ETHERS

SYNTHESIS APPLICATION

ALCOHOL CATEGORIES

Primary alcohol 1˚ ROH

Secondary alcohol 2˚ ROH

Tertiary alcohol 3˚ ROH

SYNTHESIS OF ALCOHOLS / ETHERS WITH CURRENT METHODS

Primary Alcohols

Tertiary Alcohols

Secondary Alcohols

Certain Ethers

C

OH

C C

OH

C

C C C

OH

C

C

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WILLIAMSON ETHER SYNTHESIS

GENERAL REACTION

RETROSYNTHESIS (BACKWARDS THINKING)

Synthesize butyl methyl ether with the Williamson Ether Synthesis.

Synthesize the following ether with the Williamson Ether Synthesis.

a. NaHCH3 O H

b. CH3Br

OH

a. NaH b. CH3CH2Cl

Alexander Williamson (1850)

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EXAMPLES

Give the major organic product of each reaction.

Reactants

Rate

(k1 / k2)2 1 9.5 × 102 2.2 × 105 5 × 107

2 H.D. Belitz, W. Grosch, P. Schierberle, Food Chemistry, 3rd edition, 2004, pp. 111

OHa. NaH

b. CH3CH2CH2I

Cl

a. NaH

b.CH3CH2OH

OR

O

O

O

RO

O

O

ORO

O

O

O

O

OR

O

OO

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REACTIONS OF ALCOHOLS

STRATEGY #1

DEHYDRATION

GENERAL REACTION

MECHANISM WITH 2˚ AND 3˚ ROH

CATALYTIC ACID

OH

con. H3PO4

Δ

Con. H2SO4 or H3PO4

heat (!)

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MECHANISM WITH 1˚ ROH

PRODUCT MIXTURES

APPLICATION3

3 G. Buchi, William D. Macleod, Synthesis of Patchouli Alcohol, J. Am. Chem. Soc., 1962, 84 (16), pp 3205–3206.

OH con. H2SO4heat

OH

con. H2SO4170 ˚C

OH con. H3PO4

Δ

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REACTION ENERGY DIAGRAM

1)! REACTION TO STUDY + MECHANISM

2)! BOND ENERGIES TO ESTIMATE !H

3)! ENERGY DIAGRAM

METHODS USED TO DRIVE THE REACTION

con. H2SO4heat

H C

H

C

H

H

H OH

con. H2SO4

heatH C

H

C

H

H

H OH

H C

H

C

H

H OH H+

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REARRANGEMENTS

HYDRIDE SHIFTS

1)! MECHANISM

2)! MOTIVATION FOR HYDRIDE SHIFTS

OH con. H2SO4

heat

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3)! EXAMPLE

A rearrangement occurs in this reaction. What products are likely to form from the rearrangement?

ALKYL SHIFTS

OHcon. H2SO4

Δ

OH

85% H3PO480 ˚C

OH

con. H2SO4

heat

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ALCOHOL REACTION STRATEGY #2

ROH REACTION WITH HX

GENERAL REACTION

MECHANISM WITH 2˚ OR 3˚ ROH

MECHANISM WITH 1˚ ROH

FYI: Normally HCl is used with ZnCl2 to accelerate the reaction. The Lucas Test Reagent (in lab) contains 160 g ZnCl2 in 100 mL concentrated HCl.

R OH R XNu

R Nu

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EXAMPLES

Give the expected major product for each reaction, considering plausible rearrangements.

BIOLOGICAL METHYLATIONS

Biosynthesis of morphine:

Biological methylations often use “SAM” (S-Adenosylmethionine), which is created by the reaction of methionine (an amino acid) with ATP. For example, the biosynthesis of adrenaline (“fight or flight”):

OH

HBr

OHHBr

OH

HCl

OH

HCl

OH

CH2CH3CH2CH3 HI

morphine

HO

CO2

NH3

tyrosine (an amino acid)

NH

HO

HO

HO

N

H3CO

HO

HO

CH3

OHO

OH

NCH3

HO

HO

NH2

OH

noradrenaline(norepinephrine)

N

NN

N

NH2

O

OHOH

SCH3

ONH3

O

(S)-AdenosylmethionineHO

HO

HN

OH

adrenaline(epinephrine)

CH3

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ROH REACTION WITH PBr3

GENERAL REACTION

MECHANISM + STEREOCHEM

ROH REACTION WITH SOCl2

GENERAL REACTION

MECHANISM + STEREOCHEM

OH

ClS

Cl

O

OS

H

Cl

O OS

Cl

O

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ROH REACTION WITH TSCl

GENERAL REACTION

MECHANISM + STEREOCHEM

TsCl py.

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SUMMARY AND PROBLEMS

SUMMARY

PBr3 Reaction SOCl2 Reaction Tosylate Reaction

SN2 (Inversion) SN2 (Inversion) Not SN2 (no inversion)

PROBLEMS

1)! SUBSTITUTION WITH NO INVERSION

2)! SUBSTITUTION WITH INVERSION

H3C OH H3C BrPBr3 H3C OH H3C Cl

SOCl2 H3C OH H3C OTsTsCl

py.

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3)! OTHER EXAMPLES

Give the major product for first two reactions, then devise a synthesis for the last reaction.

EPOXIDES

REACTION WITH STRONG NUCLEOPHILES

GENERAL REACTION

Nu– : OH–, OR–, SH–, CN–,

OHa. PBr3b. KOCH2CH3

OCH3

OH

a. TsCl, py.

b. NaCN

O

OH

O

SH

O NaOCH3CH3OH

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REGIOSELECTIVITY

EPOXY ADHESIVES

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STEREOSELECTIVITY

CASCADE EPOXIDATIONS

Gymnocin B is the largest contiguous polyether ring system. It can be isolated from the red tide dinoflagellate Karenia mikimotoi.4

4 Solomons, Organic Chemistry, 12th edition, 2016, p 370.

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The biosynthesis of all steroids involves a cascade reaction of squalene, initiated by opening an epoxide.

REACTION WITH WEAK NUCLEOPHILES

GENERAL REACTION

Nu: X–, H2O, ROH

REGIOSELECTIVITY

Product distribution5

5 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 457

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STEREOSELECTIVITY

EPOXIDE PROBLEMS

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REMOVAL OF CARCINOGENS6

Aflatoxins are among the most carcinogenic substances known. They are produced by certain molds (Aspergillus flavus and Aspergillus parasiticus), and are regularly found in improperly stored foods like corn, millet, peanuts, rice, sesame seeds, and wheat.

Adult humans have a high tolerance to aflatoxins, but children are susceptible. Aflatoxins are removed from the body by epoxidation followed by reaction with glutathione.

Polycyclic aromatic hydrocarbons (PAH’s) have been linked to several cancers. They can be found in smoke from solid fuels like wood, coal, and cigarettes, but are also found in the smoke from combusted diesel.

Their carcinogenic mechanisms vary. One mechanism is that enzymatic epoxidation of PAH’s creates intermediates that are reactive to the nucleophiles on DNA. Once attached to DNA, the PAH’s interfere with correct DNA replication, leading to mutations.

6 Solomons, G., Fryhle, C.B., Organic Chemistry, 8th ed., Wiley, 2004, pp. 521

O

O

O

O O

H

H

Aflatoxin B1 (fungus)

O

O

O

O O

H

H

Ocytochrome P-450

O

O

O

O O

H

H

H3NHN

NH

O

OO

OS

O

O

HOGlutathione

Two of the most carcinogenic substances knownH3N

HN

NH

O

OO

OSH

O

O

Glutathione

A polycyclic aromatic hydrocarbon

Cytochrome P-450

enzymeO

HO

OH

HO

OH

HO

DNADNA Nuc