Alcohols

Biological Activity

Nomenclature

Preparation

Reactions

Some Alcohols

CH3CH2OH HO

HO

CHCH2NH2

OH

adrenaline (epinephrine)

ethanol

CHCHNHCH3

OH

CH3

pseudephedrine

HO

H

H

H

cholesterol

HOCH2CHCH2OH

OH

glycerol

Alcohols are Found in Many Natural Products

O

HO

HO

N CH3

H

Morphine

most abundant of opium's alkaloids

Paralytic Shellfish Poisoning

N

N N

NOH

OH

H

HN

H

O

NH2O

NH

H

Saxitoxin (STX)LD50 = 2 g/kg

A possible chemical warfare agent

roughly 1000 times more toxic than saran gas or cyanide

The toxin blocks entry of sodium

required by cells to make "action potentials"

N NHO

H

O

H

O

OH

OH OH

O

HO

OH

OH

OH

OHOH

OH

OHOO

OHOH

OH

HO

OH

OH OH

OH

HO

O

OH

OH

OH

HO

OH

OH

OH

OH

OH

OH

OH

OH

OH

HO

O

OH

OH

HO

OH

OH

O O

OH

H2N

PALYTOXIN

LD50 = 0.15 g/kg

Ethanol: the Beverage

enz.

CH3CO2H + NADH + H+

NAD+

CH3CH2OH CH3CH

O

acetaldehydeLD50 = 1.9 g/Kg

ethanol

Ethanol is a central nervous system depressant - depresses brain areas responsible for judgement

(thus the illusion of stimulation)

alcohol dehydrogenase

NAD+ + NADH + H+

acetic acid

Excess NADH can cause Metabolic Problems

(+) lactic acid

pyruvic acid is normally converted to

N

sugar

C

O

NH2

CH3CCOH

OO

CH3CHCO2H

OHH+

pyruvic acidNADH (+) lactic acid

results in: acidosis and hypoglycemia

N

sugar

C

O

NH2

CH3CCOH

OO

CH3CHCO2H

OHH+

pyruvic acidNADH

glucose (gluconeogenesis)

Methanol: Not a Beverage

CH3OH

methanolHCH

O

formaldehydeLD50 = 0.07 g/Kg

NAD+ADH

+ NADH + H+

Synergistic and Metabolic Effects

• In men, ethanol lowers levels of testosterone (and sperm count) due to lack of enzymes needed for the steroid biosynthesis.

• The enzyme CYP2E1, which is responsible for converting acetaminophen into liver toxins, is activated by ethanol.

• Ethanol has a caloric value of 7.1Cal/g (fat has a value of 9 Cal/g).

• Alcohol can cause a degenerative muscle disease called alcoholic myopathy (3 times more common than cirrhosis).

Synergistic Effects

• Women will have higher BAL’s with the consumption of an equal number of drinks due to lower ADH activity and lower % H2O in blood.

• Estradiol levels increase in women (and men). This has been associated with higher incidences of heart disease and a change in bone density.

• A higher than normal concentration of Cytochrome P-450 enzymes (in the liver) are activated by ethanol creating a potential dependency.

Antitumor Agents

• Often functionalized with alcohols

• Designed to fit into specific geometic sites on proteins

• Hydrogen bonding is crucial for binding

• Water solubility is crucial for cell membrane transport

From the Bark of the Pacific Yew TreeTaxol (Paclitaxel)

O

NHO O

OH

O

O

O

OH O

O

OH

OO

O

Taxus brevifolia

How Taxol Works

• A large number of microtubules are formed at the start of cell division, and as cell division comes to an end, these microtubules are normally broken down into tubulin – a protein responsible for the cell’s structural stability.

• Taxol promotes tubulin polymerization then binds to the microtubules and inhibits their depolymerization back into tubulin.

• The cell can't divide into daughter cells and therefore the cancer can’t spread.

Tubulin with Taxol bound to one of the Functional Domains

CHIME diagram of tubulin

Taxol Causes Cells’ Tubulin Skeleton to Aggregate in Spindles

May be More Effective than Taxol

O

OH

OOHO

OS

NH

Epothilone Binhibits tubulin aggregation

DNA Cross-linker

CH3

CH3OO

O O

O

NH N

O

O

HN

HO

AcO

OH

Azinomycin BStreptomyces sahachiroi

10

21

Prevents DNA from Unraveling

O

O OH

OH

OCH3

OHO

OH

O

NH2OH

CH3

Doxorubicin (adriamycin)

Binds to DNA and inhibits the enzyme topoisomerase II

Oxidation and Reduction3 hydrocarbon oxidation levels

CH3CH3 CH2=CH2 HC CH[O] [O]

oxidation # -3 -2 -1of carbon

Oxidation levels of oxygen- halogen- and nitrogen-

containing molecules

Reduction

Oxidation

CH3CH3

CH2=CH2 HC CH

[O] [O]CH3CH2OH CH3CH=O CH3CO2H

CH3CH2Cl CH3CHCl2 CH3CCl3

CH3CH2NH2 CH3CH=NH CH3CN

[O]

Acidity of Alcohols

• Due to the electronegativity of the O atoms, alcohols are slightly acidic (pKa 16-18).

• The anion dervived by the deprotonation of an alcohol is the alkoxide.

• Alcohols also react with Na (or K) as water does to give the alkoxide (red-ox):

+ 1/2 H2NaCH3CH2O+ NaCH3CH2OH

Withdrawing Groups Enhance Acidity

CF3 C

CF3

CF3

OCF3 C

CF3

CF3

OH + NaHCO3 Na + H2CO3

alcohol pKaCH3OH 15.54

CH3CH2OH 16.00

CF3CH2OH 12.43

(CH3)3COH 18.00

(CF3)3COH 5.4

Physical Properties

CH3CH2CH3 -42 0.08 i

 

CH3OCH3 -25 1.3 ss

CH3CH2OH 78 1.7 vs

b.p. oC D sol. in H2O

Intermolecular H-Bonding

O H

O H

O H

associated liquid

intermolecular H bonding

OHH

HO

HO

H

Alcohol NomenclatureOH

3-heptanol OH5-methyl-6-hepten-2-ol

25

6

OH

CH3 CH3

3,3-dimethylcyclohexanol

OH

CH3 CH3

5,5-dimethylcyclohex-2-enol

1

2

5

1

3

3

Nomenclature

OH

(S) 2-hexanolOH

(E) 3-methyl-3-penten-2-ol

OH

OH

OH

H

(R) 2-butyl-1,4-butanediol (R) 2-butylbutane-1,4-diol

trans 3-isopropylcyclopentanol

Who am I?

HOH

4-(R)-{1-(S)[cyclohexa-2,5-dienyl]ethyl}-2-methyl-6-(E)-octen-4-ol

HOH

1 2 3

45

6

78

# chain from end closestto alcohol group

1 2

12

5

Preparation of Alcohols

• Reduction of ketones and aldehydes

• Reduction of esters and carboxylic acids

• Hydration of Alkenes

• Nucleophilic addition

– Grignard reaction

– Acetylide addition

• Substitution

• Epoxide opening

NaBH4 Reduction

R R'

O 1) NaBH4, ethanol

2) H3O+R R'

OHH

H

R R'

OH

H3O+

Some Examples

O

1) NaBH4, etherOH

CH

O

CH2OH

2) H3O+

"

Two Alcohol Products Form in Lab

(CH3)3C

ONaBH4

H

(CH3)3C

ONaBH4

O

H

(CH3)3C

(CH3)3CH

O

H

Na

Na

trans

cis

axial approach

equatorial approach

LiAlH4 Reductiona Stronger Reducing Agent

O

1) LiAlH4, THF

2) H3O+

OH

LiAlH4 will reduce: o

aldehydes to 1 alcoholso

carboxylic acids and esters to 1 alcoholso

ketones to 2 alcohols

LiAlH4 is a much stronger reducing agent

O

O

1) LiAlH4

2) H3O+ OH

+ CH3OH

1) NaBH4no reaction

2) H3O+

NaBH4 is More Selective

OH

O O1) NaBH4

2) H3O+

OH O

OH

1) LiAlH4

2) H3O+ OH

OH

Oxymercuration HydrationMarkovnikov

OH

H2) NaBH4

THF/H2O1) Hg(OAc)2 in

Hydroboration HydrationAnti-Markovnikov

3H OH

2) H2O2, NaOH

1) BH3-THF3

Organometallic ChemistryGrignard Reaction

CH3 Br + Mg MgBrCH3

CH3 MgBr" "

Grignard Reagent

excellent nucleophilevery strong base

Grignard Reagents React With Ketones to form tertiary alcohols

O

CH3MgBr in ether1)

2) H3O+

CH3HOCH3

CH3MgBrO

H3O+

+ MgBrOH

a 3 alcoholo

Grignard Reagents React With Aldehydes to form secondary alcohols

O

H

1)MgBr

in ether

2) H3O+

OH

H

Grignard Reagents React With Formaldehyde to form primary

alcohols

CH2Br

Mg, ether,

CH2 MgBr

C

O

HH

CH2CH2O MgBr

H3O+

CH2CH2OH

formaldehyde

Grignard Reagents open Epoxides

+ enant.

RCO3HO

CH3MgBr

MgBrO

CH3H3O+

OH

CH3

Grignard Reagents react (twice) with Esters to form 3o Alcohols

C

O

OCH3 1) 2 CH3MgBr

2) H3O+

C

OH

CH3CH3

C

O

CH3

OCH3

C

O

CH3

ketone

1) CH3MgBr

2) H3O+

CH3 2nd eq.

(more reactive than ester)

Grignard Summary

R MgXO R'

R''

+

epoxide

H3O+ workup

2 MgXR + C O

RO

R'H3O+ workup

R

OH

ester

C OH

R'

R

R + ROH

Grignard Summary

R MgX C O

H

H

+

+

H

R'

OCMgXR

+

R''

R'

OCMgXR

H3O+ workup

H3O+ workup

H3O+ workup

C OH

H

R

H

H

R

R'

OHC

R''

R

R'

OHC

formaldehyde

aldehyde

ketone

Grignard Reagents are exceptionally strong bases

CH3CH2CH2MgBr +

H2O

CH3OH

CH3CO2H

HC CH

CH3NH2

CH3CH2CH3

An Effective Use of the BasicityIsotopic Labeling

CH3

Br2, h

CH3 Br

Mg

ether

CH3

MgBr

D2O

CH3 D

+ MgBrOD

Synthesis

OH

?

Retrosynthetic AnalysisOH

?

MgBrBr

4-Step Synthesis

OH

MgBrBr

Br2, h

Mg in ether

1) HCHO2) H3O+

Base Catalyzed Ring-Opening of Epoxides

Base Opens Ring from Unhindered Side

O

NaOCH3 in CH3OH

OH

OCH3

OCH3

O Na

OCH3H

regenerates base catalyst

Acid Catalyzed Ring-OpeningAqueous and in Alcohol

RegiochemistryRing Opens at More Hindered Site

O

H+, CH3OH

OH

OCH3

O

HCH3OH

OH

OCH3HCH3OH

Different Regiosomers

Propose a Mechanism

Br

O

1) NaOCH3

2) heat OCH3OCH2+ NaBr

2 SN2 steps

Br

O

1) NaOCH3

2) heat OCH3OCH2+ NaBr

CH3O

Br

O

CH3O

Propose a Mechanism

O

Br

H

(cat.)H3O+

Br

OH

O

Br

H

(cat.)H3O+

Br

OH

H

Br

O

HH

HOBr

H

O

Br

H

H

H2O

Ring-Opening is Sterically Controlled

O

CH31) CH3CH2MgBr

2) H3O+ CH3

OHCH2CH3

base opens epoxide at less hindered site

Synthesize Using Only 1,2, or 3-Carbon Reagents

HC CH

OH

Retrosynthesis

OHO

+

MgBr Br

HC CH

CH3X

CH3X reduce

HBr

Mg