Structure and Synthesis of Alcohols Biological Activity Nomenclature Preparation Reactions
Dec 25, 2015
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