structure and synthesis of alcohols

Structure and Synthesis of Alcohols

Biological Activity

Nomenclature

Preparation

Reactions

© 2013 Pearson Education, Inc. Chapter 10 2

Structure of Water and Methanol

• Oxygen is sp3 hybridized and tetrahedral.• The H—O—H angle in water is 104.5°. • The C—O—H angle in methyl alcohol is 108.9°.

Examples of Classifications

CH3 C

CH3

CH3

OH*

CH3 CH

OH

CH2CH3*

CH3 CH

CH3

CH2OH*

Primary alcohol Secondary alcohol

OH

Tertiary alcohol Phenol

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

Enzymatic Oxidation of Ethanol

Ethanol oxidizes to acetaldehyde, then acetic acid, which is a normal metabolite.

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.

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

IUPAC Nomenclature

• Find the longest carbon chain containing the carbon with the —OH group.

• Drop the -e from the alkane name; add -ol.• Number the chain, giving the —OH group the

lowest number possible.• Number and name all substituents and write them

in alphabetical order.

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

© 2013 Pearson Education, Inc. Chapter 10 24

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

OHOH

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

© 2013 Pearson Education, Inc. Chapter 10 27

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 boiling point.

Physical Properties

CH3CH2CH3 -42 0.08 i

CH3OCH3 -25 1.3 ss

CH3CH2OH 78 1.7 vs

b.p. oC D sol. in H2O

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

© 2013 Pearson Education, Inc. Chapter 10 30

Formation of Alkoxide Ions

• Ethanol reacts with sodium metal to form sodium ethoxide (NaOCH2CH3), a strong base commonly used for elimination reactions.

• More hindered alcohols like 2-propanol or tert-butanol react faster with potassium than with sodium.

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

© 2013 Pearson Education, Inc. Chapter 10 32

Formation of Phenoxide Ion

The aromatic alcohol phenol is more acidic than aliphatic alcohols due to the ability of aromatic rings to delocalize the negative charge of the oxygen within the carbons of the ring.

© 2013 Pearson Education, Inc. Chapter 10 33

Charge Delocalization on the Phenoxide Ion

• The negative charge of the oxygen can be delocalized over four atoms of the phenoxide ion.

• The true structure is a hybrid between the four resonance forms.

Intermolecular H-Bonding

O H

O H

O H

associated liquid

intermolecular H bonding

OHH

HO

HO

H

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

Oxymercuration HydrationMarkovnikov

OH

H2) NaBH4

THF/H2O1) Hg(OAc)2 in

Hydroboration HydrationAnti-Markovnikov

3H OH

2) H2O2, NaOH

1) BH3-THF3

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]

© 2013 Pearson Education, Inc. Chapter 10 40

Grignard Reagents

• Formula R—Mg—X (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.

Organometallic ChemistryGrignard Reaction

CH3 Br + Mg MgBrCH3

CH3 MgBr" "

Grignard Reagent

excellent nucleophilevery strong base

© 2013 Pearson Education, Inc. Chapter 10 42

Formation of Grignard Reagents

Br

+ Mgether MgBr

CH3CHCH2CH3

Clether

+ Mg CH3CHCH2CH3

MgCl

Grignard Reagents React With Aldehydes to form secondary alcohols

O

H

1)MgBr

in ether

2) H3O+

OH

H

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 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)

Reaction of Grignards with Carboxylic Acid Derivatives

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 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

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

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)

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

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]

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

© 2013 Pearson Education, Inc. Chapter 10 62

Reducing Agents

• NaBH4 can reduce aldehydes and ketones but not esters and carboxylic acids.

• LiAlH4 is a stronger reducing agent and will reduce all carbonyls.

Synthesis

OH

?

Retrosynthetic AnalysisOH

?

MgBrBr

4-Step Synthesis

OH

MgBrBr

Br2, h

Mg in ether

1) HCHO2) H3O+

Gilman ReagentLithium dialkylcuprate

R-Br + 2 Li R + LiBr Li

2 R + CuI Cu LiLi R

R

- +

Gilman reagent

a)

b)

R can be alkyl, vinyl, aryl

Li(R)2Cu

Gilman reagents: Source of Nucleophilic R-

Coupling Reaction

Br1) 2 Li

2) CuILi(CH3CH2CH2CH2CH2)2Cu

Li(CH3CH2CH2CH2CH2)2Cu + CH3CH2Br

CH3CH2CH2CH2CH2 CH2CH3

Try these

Li Cu

2

I

a)

b)

Br

1) 2 Li 2) CuI

3)Br

Coupling occurs between original alkyl halide carbons

Li Cu

2

I

a)

b)

Br

1) 2 Li 2) CuI

3)Br

Think of it as an SN2 rxn

CuLi I

+ Cu + LiI

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