QUÍMICA ORGÁNICA 2 C.M.

PÉREZ BERUMEN

Libro Base:
QUÍMICA Química Orgánica
L. G. Wade, Jr.
ORGÁNICA 2

Capítulo 10 Diapositivas:
© 2010, Prentice Hall
Catalina M. Pérez Berumen

© CaTaLiNa, 2015.
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Structure and Synthesis Structure of Water and Methanol

of Alcohols
ì Biological Activity

ì Nomenclature

ì Preparation

ì Reactions ì Oxygen is sp3 hybridized and tetrahedral.

ì The H—O—H angle in water is 104.5°.

ì The C—O—H angle in methyl alcohol is 108.9°.

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Examples of Classifications
CH3 OH
CH3 CH CH2OH CH3 CH CH2CH3
* *
Primary alcohol Secondary alcohol

CH3
OH
CH3 C* OH
CH3
Tertiary alcohol Phenol

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Some Alcohols Alcohols are Found in

OH OH
Many Natural Products
CH3CH2OH HO CHCH2NH2 CHCHNHCH3
CH3
HO
ethanol HO
adrenaline (epinephrine) pseudephedrine
O N CH3
OH
HOCH2CHCH2OH H H
glycerol H H HO
Morphine
HO
cholesterol most abundant of opium's alkaloids
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Paralytic Shellfish Poisoning Ethanol: the Beverage

NH2 Ethanol is a central nervous system depressant
O
- depresses brain areas responsible for judgement
O (thus the illusion of stimulation)
A possible chemical warfare agent
H O
H N roughly 1000 times more toxic alcohol dehydrogenase +
N than saran gas or cyanide CH3CH2OH CH3CH + NADH + H
NH +
ethanol NAD acetaldehyde
HN N N H
OH
LD50 = 1.9 g/Kg
The toxin blocks entry of sodium
OH required by cells to make "action potentials" +
NAD
enz.
Saxitoxin (STX)
LD50 = 2 µg/kg +
CH3CO2H + NADH + H
acetic acid
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Enzymatic Oxidation of Ethanol Excess NADH can cause Metabolic

Problems
O
C
NH2
OO OH
+
N H
CH3CCOH CH3CHCO2H
sugar
NADH pyruvic acid (+) lactic acid
pyruvic acid is normally converted to
glucose (gluconeogenesis)
Ethanol oxidizes to acetaldehyde, then acetic acid, results in: acidosis and hypoglycemia
which is a normal metabolite.
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Synergistic and Metabolic Effects

Methanol: Not a Beverage
ì In men, ethanol lowers levels of testosterone (and
sperm count) due to lack of enzymes needed for the
O steroid biosynthesis.
ADH +
CH3OH HCH + NADH + H ì The enzyme CYP2E1, which is responsible for
+
methanol NAD formaldehyde converting acetaminophen into liver toxins, is
activated by ethanol.
LD50 = 0.07 g/Kg
ì Ethanol has a caloric value of 7.1Cal/g (fat has a
value of 9 Cal/g).
ì Alcohol can cause a degenerative muscle disease
called alcoholic myopathy (3 times more common
than cirrhosis).

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Synergistic Effects
IUPAC Nomenclature
ì Women will have higher BAL’s with the
consumption of an equal number of drinks due to ì Find the longest carbon chain containing the
lower ADH activity and lower % H2O in blood.
carbon with the —OH group.
ì Estradiol levels increase in women (and men).
This has been associated with higher incidences ì Drop the -e from the alkane name; add -ol.
of heart disease and a change in bone density.
ì Number the chain, giving the —OH group
ì A higher than normal concentration of the lowest number possible.
Cytochrome P-450 enzymes (in the liver) are
activated by ethanol creating a potential ì Number and name all substituents and write
dependency.
them in alphabetical order.

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Alcohol Nomenclature
Nomenclature
OH
OH
2
5
3 6
OH
3-heptanol 5-methyl-6-hepten-2-ol OH
(S) 2-hexanol (E) 3-methyl-3-penten-2-ol

2 OH OH
OH
1 1 OH
H
OH
3 5 trans 3-isopropylcyclopentanol (R) 2-butyl-1,4-butanediol
CH3 CH3 CH3 CH3 (R) 2-butylbutane-1,4-diol
3,3-dimethylcyclohexanol 5,5-dimethylcyclohex-2-enol
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Naming Diols Who am I?

ì Two numbers are needed to locate the two
—OH groups.
ì Use -diol as suffix instead of -ol.
1 2 3 4 5 6 HO
H

hexane-1,6-diol

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Boiling Points of Alcohols

1 2 3 # chain from end closest

to alcohol group
6 4
5 1 2
8
7 HO
1 H
2
ì Alcohols have higher boiling points than ethers and
5 alkanes because alcohols can form hydrogen bonds.
4-(R)-{1-(S)[cyclohexa-2,5-dienyl]ethyl}-2-methyl-6-(E)-octen-4-ol ì The stronger interaction between alcohol molecules will
require more energy to break, resulting in a higher boiling
point.

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Physical Properties Acidity of Alcohols

ì Due to the electronegativity of the O atoms, alcohols are
slightly acidic (pKa 16-18).
b.p. oC µD sol. in H2O
ì The anion dervived by the deprotonation of an alcohol is the
CH3CH2CH3 -42 0.08 i alkoxide.

ì Alcohols also react with Na (or K) as water does to give the

CH3OCH3 -25 1.3 ss alkoxide (red-ox):

CH3CH2OH 78 1.7 vs CH3CH2OH + Na CH3CH2O Na + 1/2 H2

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Formation of Alkoxide Ions Withdrawing Groups Enhance Acidity

CF3 CF3
CF3 C OH + NaHCO3 CF3 C O Na + H2CO3

CF3 CF3
alcohol pKa
ì Ethanol reacts with sodium metal to form sodium CH3OH 15.54
ethoxide (NaOCH2CH3), a strong base commonly used CH3CH2OH 16.00
for elimination reactions. CF3CH2OH 12.43
ì More hindered alcohols like 2-propanol or tert-butanol (CH3)3COH 18.00
react faster with potassium than with sodium. (CF3)3COH 5.4

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Charge Delocalization
Formation of Phenoxide Ion on the 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.
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ì The negative charge of the oxygen can be delocalized
over four atoms of the phenoxide ion.
ì The true structure is a hybrid between the four resonance
forms.
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Intermolecular H-Bonding Preparation of Alcohols

ì Reduction of ketones and aldehydes

d- d+ ì Reduction of esters and carboxylic acids

O H H
H
O ì Hydration of Alkenes
d- d+
O H associated liquid O H ì Nucleophilic addition

intermolecular H bonding H
• Grignard reaction
d- d+ H
O • Acetylide addition
O H
ì Substitution

ì Epoxide opening

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Oxymercuration Hydration Hydroboration Hydration

Markovnikov Anti-Markovnikov

1) BH3-THF H OH
3 3
1) Hg(OAc)2 in 2) H2O2, NaOH
THF/H2O OH

2) NaBH4
H

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Oxidation and Reduction Oxidation levels of

3 hydrocarbon oxidation levels oxygen- halogen- and nitrogen-
containing molecules
[O] [O]
CH3CH3 CH2=CH 2 HC CH CH2=CH2 HC CH

oxidation # -3 -2 -1 [O] CH3CH2OH

[O]
CH3CH=O
[O]
CH3CO2H
of carbon CH3CH3
CH3CH2Cl CH3CHCl2 CH3CCl3

CH3CH2NH2 CH3CH=NH CH 3CN

Oxidation

Reduction

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Organometallic Chemistry
Grignard Reagents Grignard Reaction

d - d+
CH3 Br + Mg CH3 MgBr
Grignard Reagent

ì Formula R—Mg—X (reacts like R:– +MgX).

"CH3 MgBr "
ì Ethers are used as solvents to stabilize the complex.
excellent nucleophile
ì Iodides are most reactive. Fluorides generally do not react. very strong base
ì May be formed from primary, secondary, or tertiary alkyl halides.

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Grignard Reagents React With Aldehydes to

Formation of Grignard Reagents form secondary alcohols

Br
MgBr
ether
+ Mg +
d- d
MgBr
O 1) OH
in ether
H +
2) H3O
H
Cl MgCl
ether
CH3CHCH2CH3 + Mg CH3CHCH2CH3

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Grignard Reagents React With Ketones Grignard Reagents React With

to form tertiary alcohols Formaldehyde to form primary alcohols

O
CH3 HO CH3 CH2CH2OH CH2CH2O MgBr
1) CH3MgBr in ether H 3O
+
+
+ MgBrOH
2) H3O o
a 3 alcohol d-
O
+ formaldehyde
H 3O C d+
H H
MgBrO CH3
CH2Br CH2 MgBr

Mg, ether, D

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Grignard Reagents open Epoxides Grignard Reagents react (twice) with

Esters to form 3o Alcohols
O OH
O
RCO3H C
C CH3
OCH3 1) 2 CH3MgBr CH3
+
2) H3O
CH3MgBr
CH3 2nd eq.
1) CH3MgBr
OH MgBrO O +
O 2) H3O
CH3 +
H3O CH3 C
C OCH CH3
3
CH3 ketone
+ enant.
(more reactive than ester)
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Reaction of Grignards with

Grignard Summary
H
Carboxylic Acid Derivatives H +
H3O workup
R MgX + C O R C OH
H formaldehyde H
R'
R' +
H3O workup
R MgX + C O R C OH
H aldehyde
H
R'
R' +
H3O workup
R MgX + C O R C OH
R'' ketone
R''
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Grignard Summary Solved Problem 2

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

O + OH
R' H3O workup
R MgX +
R'' R
epoxide Solution
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:
R' R'
+
H3O workup
2 R MgX + C O R C OH
RO ester
R + ROH

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Solved Problem 2 (Continued) Grignard Reagents are exceptionally

strong bases
Solution (Continued)

H2O
CH3OH
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
CH3CH2CH2MgBr + CH3CO2H CH3CH2CH3
ketones from compounds containing no more than five carbon atoms.
HC CH
CH3NH2

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An Effective Use of the Basicity Oxidation levels of

Isotopic Labeling
oxygen- halogen- and nitrogen-
containing molecules
CH3 CH3
CH3 Br
MgBr CH2=CH2 HC CH
Br2, hn Mg
[O] CH3CH2OH CH3CH=O CH3CO2H
ether [O] [O]
CH3CH3
CH3CH2Cl CH3CHCl2 CH3CCl3
D 2O
D CH3CH2NH2 CH3CH=NH CH 3CN
CH3
Oxidation

+ MgBrOD Reduction

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NaBH4 Reduction Some Examples

O O OH
1) NaBH4, ethanol H OH
+ 1) NaBH4, ether
R R' 2) H3O R R' +
2) H3O

H H 3O
+
O
"
H O CH CH2OH
R R'
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Two Alcohol Products Form in Lab LiAlH4 Reduction

a Stronger Reducing Agent
H O OH
axial approach H
O
NaBH4 1) LiAlH4, THF
O Na
(CH3)3C (CH3)3C +
2) H3O
trans

O Na
O LiAlH4 will reduce:
NaBH4 H
o
(CH3)3C
ketones to 2 alcohols
(CH3)3C o
H cis aldehydes to 1 alcohols
equatorial approach o
carboxylic acids and esters to 1 alcohols
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LiAlH4 is a much stronger NaBH4 is More Selective

reducing agent

1) LiAlH4
O OH
2) H3O
+ O O OH O
1) NaBH4
O + CH3OH +
OH 2) H3O OH

1) NaBH4
no reaction OH
+
2) H3O 1) LiAlH4
+ OH
2) H3O

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Reducing Agents Synthesis

ì NaBH4 can reduce
aldehydes and OH
ketones but not esters ?
and carboxylic acids.
ì LiAlH4 is a stronger
reducing agent and
will reduce all
carbonyls.

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Retrosynthetic Analysis 4-Step Synthesis

OH OH
?

Br2, hn 1) HCHO
+
2) H3O

Br Br Mg in ether
MgBr MgBr

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Gilman Reagent Gilman reagent R

-
Lithium dialkylcuprate Coupling Reaction
Li(R) 2Cu
1) 2 Li
Br Li(CH 3CH2CH2CH2CH2)2Cu
a) R-Br + 2 Li R Li + LiBr 2) CuI

b) 2 R Li + CuI R Cu- Li+ Li(CH 3CH2CH2CH2CH2)2Cu + CH3CH2Br

R
Gilman reagent CH3CH2CH2CH2CH2 CH2CH3
R can be alkyl, vinyl, aryl
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Coupling occurs between original alkyl

Try these halide carbons
I
I

a) Li Cu
a) Li Cu
2
2

1) 2 Li 2) CuI 1) 2 Li 2) CuI
b) b)
3) 3)
Br Br Br Br

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Base Catalyzed Ring-Opening of

Think of it as an SN2 rxn
Epoxides

Li Cu I

+ Cu + LiI

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Base Opens Ring from Unhindered Acid Catalyzed Ring-Opening

Side Aqueous and in Alcohol
O OH
OCH3
NaOCH3 in CH3OH

H OCH3
O Na
OCH3 regenerates base catalyst

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Regiochemistry Different Regiosomers

Ring Opens at More Hindered Site
+
H , CH3OH

O OH
OCH3

OH
O
OCH3
CH3OH H
CH3OH H
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Propose a Mechanism 2 SN2 steps

CH3O
1) NaOCH3
Br
1) NaOCH3 2) heat + NaBr
Br O CH3OCH2 O
2) heat + NaBr
O CH3OCH2 O

Br
CH3O
O

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Propose a Mechanism +
Br
H3O (cat.)
Br O
O
Br H H
+
H3O (cat.) H
Br O
O Br
H H
H 2O O
H
H

Br Br
HO
H O
H H
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Ring-Opening is Sterically Synthesize Using Only 1,2, or 3-Carbon

Controlled Reagents

CH2CH3
O OH OH
1) CH3CH2MgBr
CH3 CH3
2) H3O
+ HC CH

base opens epoxide at less hindered site

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Retrosynthesis

d+
OH
O d-
MgBr Mg Br

HC CH

CH3X HBr
CH3X reduce

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