alcohols-structure and synthesis 2

8/11/2019 Alcohols-structure and Synthesis 2

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Structure and Synthesis

of AlcoholsBiological Activity

NomenclaturePreparation

Reactions


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2013 Pearson Education, Inc. Chapter 10 2

Structure of Water and Methanol

Oxygen is sp3

hybridized and tetrahedral. The HOH angle in water is 104.5.

The COH angle in methyl alcohol is 108.9.


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Examples of Classifications

C H3 C

C H3

C H3

O H*

CH3 C H

O H

C H2C H3*

C H3 C H

C H3

C H2O H

*Primary alcohol Secondary alcohol

OH

Tertiary alcohol Phenol


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Some Alcohols

CH3CH2OH HO

HO

CHCH2NH2

OH

adrenaline (epinephrine)

ethanol

CHCHNHCH3

OH

CH3

pseudephedrine

HO

H

H

H

cholesterol

HOCH2CHCH2OH

OH

glycerol


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Alcohols are Found in Many

Natural Products

O

HO

HO

N CH3

H

Morphine

most abundant of opium's alkalo


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Paralytic Shellfish Poisoning

N

N N

N

OH

OH

H

HN

H

O

NH2O

NH

H

Saxitoxin (STX)LD50= 2 g/kg

A possible chemical warfare agent

roughly 1000 times more toxicthan saran gas or cyanide

The toxin blocks entry of sodium

requi red by cel ls to make " action potentials


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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


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Ethanol: the Beverage

enz.

CH3CO2H + NADH + H+

NAD+

CH3CH2OH CH3CH

O

acetaldehyde

LD50= 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


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Enzymatic Oxidation of Ethanol

Ethanol oxidizes to acetaldehyde, then acetic acid,

which is a normal metabolite.


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Excess NADH can cause

Metabolic Problems

(+) lactic aci

pyruvic acid is normally converted to

N

sugar

C

O

NH2

CH3CCOH

OO

CH3CHCO2H

OHH

+

pyruvic acidNADH (+) lactic aci

results in: acidosisand hypoglycemia

N

sugar

C

O

NH2

CH3CCOH

OO

CH3CHCO2H

OHH

+

pyruvic acidNADH

glucose (gluconeogenesis)


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Methanol: Not a Beverage

CH3OH

methanol

HCH

O

formaldehyde

LD50= 0.07 g/Kg

NAD+

ADH+ NADH + H

+


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Synergistic and Metabolic

Effects In men, ethanol lowers levels of testosterone (and

sperm count) due to lack of enzymes needed forthe steroid biosynthesis.

The enzyme CYP2E1, which is responsible forconverting acetaminophen into liver toxins, isactivated 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 commonthan cirrhosis).


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Synergistic Effects

Women will have higher BALs with theconsumption of an equal number of drinks due tolower ADH activity and lower % H2O in blood.

Estradiol levels increase in women (and men).

This has been associated with higher incidences ofheart disease and a change in bone density.

A higher than normal concentration ofCytochrome P-450 enzymes (in the liver) are

activated by ethanol creating a potentialdependency.


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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


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From the Bark of the Pacific Yew Tree

Taxol (Paclitaxel)

O

NHO O

OH

O

O

O

OH O

O

OH

OO

O

Taxus brevi f ol ia


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How Taxol Works

A large number of microtubulesare formed atthe 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 cells structural stability.

Taxolpromotes 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 cant spread.


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May be More Effective than Taxol

O

OH

OOHO

O

S

N

H

Epothilone B

inhibits tubulin aggregation


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DNA Cross-linker

CH3

CH3OO

O O

O

NH N

O

O

HN

HO

AcO

OH

Azinomycin BStreptomyces sahachi roi

10

21


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Prevents DNA from Unraveling

O

O OH

OH

OCH3

OHO

OH

O

NH2OH

CH3

Doxorubicin (adriamycin)

Binds to DNA and inhibits the enzyme topoisomera


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IUPAC Nomenclature

Find the longest carbon chain containing the

carbon with theOH group.

Drop the -efrom the alkane name; add -ol. Number the chain, giving theOH group the

lowest number possible.

Number and name all substituents and write them

in alphabetical order.


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Alcohol Nomenclature

OH

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

25

6

OH

CH3 CH3

3,3-dimethylcyclohexanol

OH

CH3 CH3

5,5-dimethylcyclohex-2-eno

1

2

5

1

3

3


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Nomenclature

OH

(S) 2-hexanol

OH

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

OH

OH

OH

H

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

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

trans3-isopropylcyclopentanol


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Naming Diols

Two numbers are needed to locate the two

OH groups.

Use -diol as suffix instead of -ol.

hexane-1,6-diol

1 2 3 4 5 6


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Who am I?

HOH


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

HOH

1 2 3

456

7

8

# chain from end closestto alcohol group

1 2

12

5


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Boiling Points of Alcohols

Alcohols have higher boiling points than ethers and

alkanes because alcohols can form hydrogen bonds. The stronger interaction between alcohol molecules will

require more energy to break, resulting in a higher boilingpoint.


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Physical Properties

CH3CH2CH3 -42 0.08 i

CH3OCH3 -25 1.3 ss

CH3CH2OH 78 1.7 vs

b.p. oC D sol. in H2O


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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 H 2NaCH3CH2O+ NaCH3CH2OH


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Withdrawing Groups Enhance

Acidity

CF3 C

CF3

CF3

OCF3 C

CF3

CF3

OH + NaHCO3 Na + H2CO3

alcohol pKa

CH3OH 15.54

CH3CH2OH 16.00

CF3CH2OH 12.43

(CH3)3COH 18.00

(CF3)3COH 5.4


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Formation of Phenoxide Ion

The aromatic alcoholphenol is more acidicthan aliphaticalcohols due to the ability of aromatic rings to delocalize

the negative charge of the oxygen within the carbons of the

ring.


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Charge Delocalization on the

Phenoxide Ion

The negative charge of the oxygen can be delocalized overfour atoms of the phenoxide ion.

The true structure is a hybridbetween the four resonanceforms.


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Intermolecular H-Bonding

O H

O H

O H

associated liquid

intermolecular H bonding

O

HH

H

O

HO

H


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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


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Oxymercuration Hydration

Markovnikov

OH

H

2) NaBH4

THF/H2O1) Hg(OAc)2in


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Hydroboration Hydration

Anti-Markovnikov

3

H OH

2) H2O2, NaOH

1) BH3-THF3


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Oxidation and Reduction

3 hydrocarbon oxidation levels

CH3CH3 CH2=CH 2 HC CH[O] [O]

oxidation # -3 -2 -1of carbon


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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]


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Grignard Reagents

Formula RMgX (reacts like R:+MgX).

Ethers are used as solvents to stabilize the complex.

Iodides are most reactive. Fluorides generally do not react.

May be formed from primary, secondary, or tertiary alkyl

halides.


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Organometallic Chemistry

Grignard Reaction

CH3 Br + Mg MgBrCH3

CH3 MgBr" "

Grignard Reagent

excellent nucleophilevery strong base


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Formation of GrignardReagents

Br

+ Mgether

MgBr

CH3CHCH2CH3

Cl

ether+ Mg CH3CHCH2CH3

MgCl


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Grignard Reagents React With

Aldehydesto form secondary alcohols

O

H

1)MgBr

in ether

2) H3O+

OH

H


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Ketonesto form tertiary alcoholsO

CH3MgBr in ether1)

2) H3O+

CH3HOCH3

CH3MgBrO

H3O+

+ MgBrOHa 3 alcohol

o



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Formaldehydeto form primary

alcohols

CH2Br

Mg, ether,

CH2MgBr

C

O

HH

CH2CH2O MgBr

H3O+

CH2CH2OH

formaldehyd


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Grignard Reagents open

Epoxides

+ enant.

RCO3HO

CH3MgBr

MgBrO

CH3H3O+

OH

CH3


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Grignard Reagentsreact (twice) with

Estersto form3oAlcohols

C

O

OCH3 1) 2 CH3MgBr

2) H3O+

C

OH

CH3CH3

C

O

CH3

OCH3C

O

CH3

ketone

1) CH3MgBr

2) H3O+

CH3 2nd eq.

(more reactive than ester)


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Reaction of Grignards with

Carboxylic Acid Derivatives

G i S


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Grignard Summary

R MgX C OH

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


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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


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Show how you would synthesize the following alcohol from compounds containing no more than five

carbon atoms.

This is a tertiary alcohol; any one of the three alkyl groups might be added in the form of a Grignard

reagent. We can propose three combinations of Grignard reagents with ketones:

Solved Problem 2

Solution


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Any of these three syntheses would probably work, but only the third begins with fragments containing

no more than five carbon atoms. The other two syntheses would require further steps to generate the

ketones from compounds containing no more than five carbon atoms.

Solved Problem 2 (Continued)

Solution (Continued)


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Grignard Reagents are

exceptionallystrong bases

CH3CH2CH2MgBr +

H2O

CH3OH

CH3CO2H

HC CH

CH3NH2

CH3CH2CH3


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An Effective Use of the Basicity

IsotopicLabelingCH3

Br2, h

CH3 Br

Mg

ether

CH3

MgBr

D2O

CH3 D

+ MgBrOD

O id ti l l f


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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]


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NaBH4Reduction

R R'

O1) NaBH4, ethanol

2) H3O+

R R'

OHH

H

R R'

OH

H3O+


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Some Examples

O

1) NaBH4, ether

OH

CHO

CH2OH

2) H3O+

"


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Two Alcohol Products Form in Lab

(CH3)3C

O

NaBH4

H

(CH3)3C

ONaBH4

O

H

(CH3)3C

(CH3)3CH

O

H

Na

Na

trans

cis

axial approach

equatorial approach


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LiAlH4Reductiona Stronger Reducing Agent

O

1) LiAlH4, THF

2) H3O+

OH

LiAlH4will reduce:o

aldehydes to 1 alcoholso

carboxylic acids and esters to 1 alcoo

ketones to 2 alcohols


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LiAlH4is a much stronger

reducing agent

O

O

1) LiAlH 4

2) H3O+

OH

+ CH3OH

1)NaBH4no reaction

2) H3O+


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NaBH4is More Selective

OH

O O1) NaBH4

2) H3O+

OH O

OH

1) LiAlH4

2) H3O+ OH

OH


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Reducing Agents

NaBH4can reduce

aldehydes and ketones

but not esters and

carboxylic acids.

LiAlH4is a stronger

reducing agent and

will reduce allcarbonyls.


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Synthesis

OH

?


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Retrosynthetic Analysis

OH

?

MgBrBr


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4-Step Synthesis

OH

MgBrBr

Br2, h

Mg in ether

1) HCHO

2) H3O+


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Gilman Reagent

Lithium dialkylcuprate

R-Br + 2 Li R + LiBrLi

2 R + CuI Cu LiLi R

R

- +

Gilman reagent

a)

b)

Rcan be alkyl, vinyl, aryl

Li(R)2Cu

Gil t


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Gilman reagents:

Source of Nucleophilic R-

Coupling Reaction

Br

1) 2 Li

2) CuI

Li(CH3CH2CH2CH2CH2)2Cu

Li(CH3CH2CH2CH2CH2)2Cu + CH3CH2Br

CH3CH2CH2CH2CH2 CH2CH3


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Try these

Li Cu

2

I

a)

b)

Br

1) 2 Li 2) CuI

3)

Br


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Coupling occurs between original

alkyl halide carbons

Li Cu2

I

a)

b)

Br

1) 2 Li 2) CuI

3)

Br


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B O Ri f


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Base Opens Ring from

Unhindered Side

O

NaOCH3in CH3OH

OH

OCH3

OCH3

O Na

OCH3H

regenerates base catalyst

Acid Catalyzed Ring-Opening


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Acid Catalyzed Ring-OpeningAqueous and in Alcohol

Regiochemistry


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RegiochemistryRing Opens at More Hindered Site

O

H+, CH3OH

OH

OCH3

O

HCH3OH

OH

OCH3HCH3OH


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Different Regiosomers


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Propose a Mechanism

Br

O

1) NaOCH3

2) heat OCH3OCH2

+ NaBr


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2 SN2 steps

Br

O

1) NaOCH3

2) heat OCH3OCH2+ NaBr

CH3O

Br

O

CH3O


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Propose a Mechanism

O

Br

H

(cat.)H3O+

Br

OH


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O

Br

H

(cat.)H3O+

Br

OH

H

Br

O

H

H

HOBr

H

O

Br

H

H

H2O

Ring-Opening is Sterically


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Ring-Opening is Sterically

Controlled

O

CH31)CH3CH2MgBr

2) H3O+ CH3

OH

CH2CH3

base opens epoxide at less hindered site

S h i U i O l 1 2


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Synthesize Using Only 1,2, or

3-Carbon Reagents

HC CH

OH


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Retrosynthesis

OHO

+

MgBrBr

HC CH

CH3X

CH3Xreduce

HBr

Mg

alcohols-structure and synthesis 2

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