Transcript Alcohols - La Salle University

Structure and Synthesis
of Alcohols
Biological Activity
Nomenclature
Preparation
Reactions
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°.
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Examples of Classifications
OH
CH3
CH3
CH CH2OH
*
Primary alcohol
CH3
CH3
C* OH
CH3
CH CH2CH3
*
Secondary alcohol
OH
CH3
Tertiary alcohol
Phenol
Some Alcohols
CH3CH2OH
HO
OH
OH
CHCH2NH2
CHCHNHCH3
CH3
ethanol
HO
adrenaline (epinephrine)
OH
H
HOCH2CHCH2OH
glycerol
H
HO
H
cholesterol
pseudephedrine
Alcohols are Found in Many
Natural Products
HO
N CH3
O
H
HO
Morphine
most abundant of opium's alkaloids
Paralytic Shellfish Poisoning
NH2
O
O
H
HN
H
N
N
NH
N
A possible chemical warfare agent
roughly 1000 times more toxic
than saran gas or cyanide
N H
OH
The toxin blocks entry of sodium
OH required by cells to make "action potentials"
Saxitoxin (STX)
LD 50 = 2 g/kg
OH
O
O
OH
OH
HO
OH
O
H2N
OH
OH
OH
OH
HO
PALYTOXIN
LD 50 = 0.15 g/kg
OH
OH
OH
OH
OH
OH
O
HO
O
N
N
H
H
HO
OH
OH
OH
OH
OH
O
OH
OH
OH
OH
HO
OH
O
O
O
OH
HO
OH
OH
OH
OH
HO
OH
OH
OH
OH
OH
Ethanol: the Beverage
Ethanol is a central nervous system depressant
- depresses brain areas responsible for judgement
(thus the illusion of stimulation)
alcohol dehydrogenase
CH 3CH 2OH
ethanol
NAD
+
O
CH 3CH + NADH + H
acetaldehyde
LD 50 = 1.9 g/Kg
NAD
enz.
+
CH 3CO 2H + 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
O
C
NH2
OO
N
CH3CCOH
H
OH
+
CH3CHCO2H
sugar
NADH
pyruvic acid
(+) lactic acid
pyruvic acid is normally converted to
glucose (gluconeogenesis)
results in: acidosis and hypoglycemia
Methanol: Not a Beverage
CH3OH
methanol
ADH
NAD
+
O
+
HCH + NADH + H
formaldehyde
LD 50 = 0.07 g/Kg
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 Tree
Taxol (Paclitaxel)
O
O
O
NH
OH
O
O
O
OH
O
OH O O
O
Taxus brevifolia
O
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
Epothilone B
inhibits tubulin aggregation
O
S
H
OH
N
O
O
OH
O
DNA Cross-linker
21
O
CH3O
O
O
O
O
N
CH3
OH
N
H
AcO
H
N
10
HO
Azinomycin B
Streptomyces sahachiroi
O
Prevents DNA from Unraveling
O
O
OH
OH
OH
OCH3 O
OH
O
CH3
NH2
Doxorubicin (adriamycin)
OH
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 Nomenclature
OH
3
3-heptanol
6
2
5
5-methyl-6-hepten-2-ol OH
2
OH
1
1
3
CH3
CH3
3,3-dimethylcyclohexanol
OH
CH3
5
CH3
5,5-dimethylcyclohex-2-enol
Nomenclature
OH
OH
(E) 3-methyl-3-penten-2-ol
(S) 2-hexanol
OH
OH
trans 3-isopropylcyclopentanol
H
OH
(R) 2-butyl-1,4-butanediol
(R) 2-butylbutane-1,4-diol
Naming Diols
• Two numbers are needed to locate the two
—OH groups.
• Use -diol as suffix instead of -ol.
1
2
3
4
5
6
hexane-1,6-diol
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Who am I?
HO
H
1
2
6
4
5
8
7
# chain from end closest
to alcohol group
3
HO
2
1
1
H
2
5
4-(R)-{1-(S)[cyclohexa- 2,5-dienyl]ethyl}-2-methyl-6-(E)-octen-4-ol
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.
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Physical Properties
b.p. oC
D
sol. in H2O
CH3CH2CH3
-42
0.08
i
CH3OCH3
-25
1.3
ss
CH3CH2OH
78
1.7
vs
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):
CH3CH2OH + Na
CH3CH2O Na + 1/2 H2
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.
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Withdrawing Groups Enhance
Acidity
CF3
CF3
CF3
C OH + NaHCO3
CF3
CF3
alcohol
CH3OH
CH3CH2OH
CF3CH2OH
(CH3)3COH
(CF3)3COH
C O Na + H2CO3
CF3
pKa
15.54
16.00
12.43
18.00
5.4
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.
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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.
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Intermolecular H-Bonding
 
O H
H
H
 
O H
 
O H
O
associated liquid
intermolecular H bonding
O H
H
H
O
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 Hydration
Markovnikov
1) Hg(OAc) 2 in
THF/H2O
2) NaBH4
OH
H
Hydroboration Hydration
Anti-Markovnikov
3
1) BH3-THF
2) H2O2, NaOH
H OH
3
Oxidation and Reduction
3 hydrocarbon oxidation levels
CH3CH3
oxidation #
of carbon
-3
[O]
CH2=CH2
-2
[O]
HC
-1
CH
Oxidation levels of
oxygen- halogen- and nitrogencontaining molecules
CH2=CH2
CH3CH3
[O]
CH3CH2OH
HC
[O]
CH
CH3CH=O
[O]
CH3CO2H
CH3CH2Cl
CH 3CHCl2
CH3CCl3
CH3CH2NH2
CH3CH=NH
CH3CN
Oxidation
Reduction
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.
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Organometallic Chemistry
Grignard Reaction
CH3
Br + Mg
"CH3 MgBr "
excellent nucleophile
very strong base
 
CH3 MgBr
Grignard Reagent
Formation of Grignard Reagents
Br
+
Mg
ether
Cl
CH3CHCH2CH3
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+
Mg
ether
Chapter 10
MgBr
MgCl
CH3CHCH2CH3
42
Grignard Reagents React With
Aldehydes to form secondary alcohols
O

 
MgBr
in ether
1)
H
OH
+
2) H3O
H
Grignard Reagents React With
Ketones to form tertiary alcohols
O
CH3
1) CH3MgBr in ether
2) H3O
HO
+ MgBrOH
+
o
a 3 alcohol
H3O
MgBrO
CH3
CH3
+
Grignard Reagents React With
Formaldehyde to form primary
alcohols
CH2CH2O MgBr
CH2CH2OH
H3O
+
O

C 
H
H
formaldehyde
CH2 MgBr
CH2Br
Mg, ether, 
Grignard Reagents open
Epoxides
O
RCO3H
CH3MgBr
OH
MgBrO
CH3
+ enant.
H 3O
+
CH3
Grignard Reagents react (twice) with
Esters to form 3o Alcohols
O
OH
C
C CH
3
CH3
OCH3
1) 2 CH3MgBr
2) H3O
+
CH3
O
C OCH
3
CH3
2nd eq.
1) CH3MgBr
+
2) H3O
O
C
CH3
ketone
(more reactive than ester)
Reaction of Grignards with
Carboxylic Acid Derivatives
Grignard Summary
H
H
R
MgX
+
+
C
O
H3O workup
R
H formaldehyde
R
MgX
R'
+
O
R'
H3O workup
R
H aldehyde
R
MgX
R'
+
C
R''
ketone
C
OH
H
R'
+
O
OH
H
+
C
C
H3O workup
R
C
R''
OH
Grignard Summary
R
O
H3O workup
R'
MgX +
epoxide
R''
R
R'
2 R
MgX
+
OH
+
R'
+
C
O
RO ester
H3O workup
R
C
OH
R + ROH
Solved Problem 2
Show how you would synthesize the following alcohol from compounds containing no more than five
carbon atoms.
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:
Solved Problem 2 (Continued)
Solution (Continued)
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.
Grignard Reagents are
exceptionally strong bases
H2O
CH3OH
CH3CH2CH2MgBr +
CH3CO2H
HC
CH
CH3NH2
CH3CH2CH3
An Effective Use of the Basicity
Isotopic Labeling
CH3
CH3
CH3
Br
MgBr
Mg
Br 2, h
ether
D 2O
CH3
D
+ MgBrOD
Oxidation levels of
oxygen- halogen- and nitrogencontaining molecules
CH2=CH2
CH3CH3
[O]
CH3CH2OH
HC
[O]
CH
CH3CH=O
[O]
CH3CO2H
CH3CH2Cl
CH 3CHCl2
CH3CCl3
CH3CH2NH2
CH3CH=NH
CH3CN
Oxidation
Reduction
NaBH4 Reduction
O
R
1) NaBH4, ethanol
R'
2) H3O
+
H
H
OH
R
R'
H 3O
H
R
O
R'
+
Some Examples
O
OH
1) NaBH 4, ether
2) H3O
O
CH
+
"
CH2OH
Two Alcohol Products Form in Lab
O
H
axial approach
NaBH4
(CH3)3C
H
O Na
(CH3)3C
trans
O Na
O
NaBH4
(CH3)3C
H
(CH3)3C
H
equatorial approach
cis
LiAlH4 Reduction
a Stronger Reducing Agent
OH
O
1) LiAlH 4, THF
2) H3O
+
LiAlH 4 will reduce:
o
ketones to 2 alcohols
o
aldehydes to 1 alcohols
o
carboxylic acids and esters to 1 alcohols
LiAlH4 is a much stronger
reducing agent
1) LiAlH 4
O
OH
+
2) H3O
+ CH3OH
O
1) NaBH4
+
2) H3O
no reaction
NaBH4 is More Selective
O
O
1) NaBH4
OH
OH
+
2) H3O
O
OH
OH
1) LiAlH 4
+
2) H3O
OH
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.
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Synthesis
OH
?
Retrosynthetic Analysis
OH
?
Br
MgBr
4-Step Synthesis
OH
1) HCHO
+
2) H3O
Br 2, h
Br
Mg in ether
MgBr
Gilman Reagent
Lithium dialkylcuprate
Li(R) 2Cu
a)
R-Br + 2 Li
b) 2 R
Li
+ CuI
R Li
R
Cu-
+ LiBr
Li+
R
Gilman reagent
R can be alkyl, vinyl, aryl
Gilman reagents:
Source of Nucleophilic R
Coupling Reaction
1) 2 Li
Br
2) CuI
Li(CH 3CH2CH2CH2CH2)2Cu
Li(CH 3CH2CH2CH2CH2)2Cu + CH3CH2Br
CH3CH2CH2CH2CH2
CH2CH3
Try these
I
a) Li
Cu
2
1) 2 Li 2) CuI
b)
3)
Br
Br
Coupling occurs between original
alkyl halide carbons
I
a) Li
Cu
2
1) 2 Li 2) CuI
b)
3)
Br
Br
Think of it as an SN2 rxn
Li
Cu
I
+ Cu
+ LiI
Base Catalyzed Ring-Opening
of Epoxides
Base Opens Ring from
Unhindered Side
OH
O
NaOCH3 in CH 3OH
H
OCH3
O Na
OCH3
regenerates base catalyst
OCH3
Acid Catalyzed Ring-Opening
Aqueous and in Alcohol
Regiochemistry
Ring Opens at More Hindered Site
+
H , CH3OH
OH
O
OCH3
OH
O
CH3OH
H
OCH3
CH3OH
H
Different Regiosomers
Propose a Mechanism
Br
O
1) NaOCH3
2) heat
CH3OCH2
O
+ NaBr
2 SN2 steps
CH3O
Br
1) NaOCH3
2) heat
O
Br
CH3O
O
CH3OCH2
O
+ NaBr
Propose a Mechanism
Br
+
H3O (cat.)
Br
H
O
O
H
Br
+
H3O (cat.)
Br
O
O
H
H
H
Br
H2O
H
O
H
Br
H
O
H
HO
Br
H
Ring-Opening is Sterically
Controlled
CH2CH3
OH
O
CH3
1) CH3CH2MgBr
+
2) H3O
base opens epoxide at less hindered site
CH3
Synthesize Using Only 1,2, or
3-Carbon Reagents
OH
HC
CH
Retrosynthesis
+
OH
O 
MgBr
HC
Mg
Br
CH
HBr
CH3X
CH3X
reduce