26 26-1 organic chemistry william h. brown & christopher s. foote
TRANSCRIPT
2626
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Organic Organic Chemistry Chemistry
William H. Brown &William H. Brown &
Christopher S. FooteChristopher S. Foote
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LipidsLipids
Chapter 26Chapter 26
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LipidsLipids Lipids:Lipids: a heterogeneous class of naturally
occurring organic compounds classified together on the basis of common solubility properties• they are insoluble in water but soluble in aprotic
organic solvents, including diethyl ether, methylene chloride, and acetone
Lipids include• triglycerides, phospholipids, prostaglandins,
prostacyclins, and fat-soluble vitamins• cholesterol, steroid hormones, and bile acids
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TriglyceridesTriglycerides Triglyceride:Triglyceride: an ester of glycerol with three fatty
acids
A triglyceride
CH2OCR
CH2OCR''
R'COCH1. NaOH, H2O
2. HCl, H2O
CH2OH
CH2OH
1,2,3-Propanetriol(Glycerol, glycerin)
+
RCOOH
R'COOH
R''COOH
Fatty acids
O
HOCH
O
O
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Fatty AcidsFatty Acids Fatty acid:Fatty acid: an unbranched chain carboxylic acid
derived from hydrolysis of animal fats, vegetable oils, or membrane phospholipids• nearly all have an even number of carbon atoms, most
between 12 and 20, in an unbranched chain• the three most abundant are palmitic (16:0), stearic
acid (18:0), and oleic acid (18:1)• in most unsaturated fatty acids, the cis isomer
predominates; the trans isomer is rare• unsaturated fatty acids have lower melting points than
their saturated counterparts; the greater the degree of unsaturation, the lower the melting point
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Unsaturated Fatty Acids
Saturated Fatty Acids
20:4
18:3
18:2
18:1
16:1
20:0
18:0
16:0
14:0
12:0
Carbon Atoms/Double Bonds*
Melting Point(°C)
Common Name
-49
-11
-5
16
1
77
70
63
58
44
Arachidonic acid
Linolenic acid
Linoleic acid
Oleic acid
Palmitoleic acid
Arachidic acid
Stearic acid
Palmitic acid
Myristic acid
Lauric acid
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TriglyceridesTriglycerides Physical properties depend on the fatty acid
components• melting point increases as the number of carbons in
its hydrocarbon chains increases and as the number of double bonds decreases
• triglycerides rich in unsaturated fatty acids are generally liquid at room temperature and are called oilsoils
• triglycerides rich in saturated fatty acids are generally semisolids or solids at room temperature and are called fatsfats
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TriglyceridesTriglycerides The lower melting points of triglycerides rich in
unsaturated fatty acids are related to differences in their three-dimensional shape• hydrocarbon chains of saturated fatty acids can lie
parallel with strong dispersion forces between their chains; they pack into well-ordered, compact crystalline forms and melt above room temperature
• because of the cis configuration of the double bonds in unsaturated fatty acids, their hydrocarbon chains have a less ordered structure and dispersion forces between them are weaker; these triglycerides have melting points below room temperature
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Soaps and DetergentsSoaps and Detergents Natural soaps are prepared by boiling lard or
other animal fat with NaOH, in a reaction called saponification (Latin, sapo, soap)
Sodium soaps
1,2,3-Propanetriol(Glycerol; Glycerin)
A triglyceride(a triester of glycerol)
+
saponification+CH
CH2OCR
CH2OCR
CHOH
CH2OH
CH2OH
RCO 3NaOH
3RCO- Na
+
O
O
O
O
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Soaps and DetergentsSoaps and Detergents Soaps clean by acting as emulsifying agents
• their long hydrophobic hydrocarbon chains are insoluble in water and tend to cluster in such a way as to minimize their contact with water
• their polar hydrophilic carboxylate groups, on the other hand, tend to remain in contact with the surrounding water molecules
• driven by these two forces, soap molecules spontaneously cluster into micelles
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Soaps and DetergentsSoaps and Detergents• micelle:micelle: a spherical arrangement of organic molecules
in water clustered so that their hydrophobic parts are buried inside the sphere and their hydrophilic parts are on the surface of the sphere and in contact with water
• when soap is mixed with water-insoluble grease, oil, and fats, the nonpolar parts of the soap micelles “dissolve” these nonpolar dirt molecules and they are carried away in the polar wash water
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Soaps and DetergentsSoaps and Detergents Soaps form water-insoluble salts when used in
water containing Ca(II), Mg(II), and Fe(III) ions (hard waterhard water)
+
+
A sodium soap(soluble in water as micelles)
Calcium salt of a fatty acid(insoluble in water)
2CH3(CH2)1 4COO- Na+Ca2 +
[CH3 (CH2)14COO-]2 Ca2+2Na+
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Synthetic DetergentsSynthetic Detergents The design criteria for a good detergent are
• a long hydrocarbon tail of 12 to 20 carbons• a polar head group that does not form insoluble salts
with Ca(II), Mg(II), or Fe(III) ions
The most widely used synthetic detergents are the linear alkylbenzenesulfonates (LAS)
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Soaps and DetergentsSoaps and Detergents
Also added to detergent preparations are• foam stabilizers• bleaches• optical brighteners
Dodecylbenzene
Sodium 4-dodecylbenzenesulfonate(an anionic detergent)
CH3(CH2 )10 CH2
CH3(CH2 )10 CH2 SO3-
Na+
1. H2SO4
2. NaOH
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ProstaglandinsProstaglandins Prostaglandins:Prostaglandins: a family of compounds that have
the 20-carbon skeleton of prostanoic acid
23
45
67
89
20
10
11 1213
1415
1617
1819
1
Prostanoic acid
COOH
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ProstaglandinsProstaglandins Prostaglandins are not stored in tissues as such,
but are synthesized from membrane-bound 20-carbon polyunsaturated fatty acids in response to specific physiological triggers• one such polyunsaturated fatty acid is arachidonic
acid
COOH
Arachidonic acid1514
89
11 12
6 5
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ProstaglandinsProstaglandins• among the prostaglandins synthesized biochemically
from arachidonic acid are
PGE2
11
9
15
15
9
11
PGF2α
HO
COOH
HO H
COOH
HO
HOHO H
O
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ProstaglandinsProstaglandins Research on the involvement of PGs in
reproductive physiology has produced several clinically useful derivatives• 15-methyl-PGF2α is used as a therapeutic abortifacient
COOH
HO
HOHO CH3
15
9
11
15-Methyl-PGF2α
extra methyl group
-15at carbon
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ProstaglandinsProstaglandins• the PGE1 analog, misoprostol, is used to prevent the
ulceration associated with the use of aspirin-like NSAIDs
1615
Misoprostol
PGE1
1516
COOCH3
HO
O
HO
CH3
HO HHO
OCOOH
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EicosanoidsEicosanoids The prostaglandins are members of an even
larger family of compounds called eicosanoidseicosanoids, all of which contain 20 carbons and are derived from polyunsaturated fatty acids
COOHO
OHO
H
H
(a potent vasoconstrictor)Thromboxane A2
189
112015
12
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EicosanoidsEicosanoids Leukotrienes are found primarily in white blood
cells. One function is constriction of smooth muscles, especially those of the lungs
S
HO
COOH
HN
NH
NH2
O
O
COOH
COOH
glycine
L-glutamic acidL-cysteine
20
14
11 9 76 5
1
Leukotriene C4 (LTC4)(a smooth muscle constrictor)
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SteroidsSteroids Steroids:Steroids: a group of plant and animal lipids that
have this tetracyclic ring structure
The features common to the ring system of most naturally occurring steroids are illustrated on the next screen
A B
C D
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SteroidsSteroids• the fusion of rings is trans and each atom or group at
a ring junction is axial• the pattern of atoms or groups along the ring
junctions is nearly always trans-anti-trans-anti-trans• the steroid system is nearly flat and quite rigid• most have have axial methyl groups at C-10 and C-13
HCH3
HH
CH3
H
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CholesterolCholesterol
H3C
HO
H3C
H H
H
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AndrogensAndrogens Androgens - male sex hormones
• synthesized in the testes• responsible for the development of male secondary
sex characteristics
AndrosteroneTestosteroneO
HOH
H
H3C H
H
H3C H3C
H
HH3C
H
O
HO
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Anabolic SteroidsAnabolic Steroids Among the synthetic anabolic steroids are
StanozololMethandrostenolone
17
21
O
CH3
OH
H
H3C H
H
H3C H3C
H
HH3C
H
OHCH3
HNN
H
A
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EstrogensEstrogens Estrogens - female sex hormones
• synthesized in the ovaries• responsible for the development of female secondary
sex characteristics and control of the menstrual cycle
Progesterone Estrone
H3C
H
HH3C
H
C=OH
O
CH3
O
HO
H
H
H
H3C
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Synthetic EstrogensSynthetic Estrogens Progesterone-like analogs are used in oral
contraceptives
"Nor" refers to the absence of a methyl group here. The methyl group is present in ethindrone
Norethindrone
H3C
H
HH
OH
HOC CH
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Glucorticoid HormonesGlucorticoid Hormones• synthesized in the adrenal cortex• regulate metabolism of carbohydrates• decrease inflammation• involved in the reaction to stress
CortisolCortisone
C=O
CH2OH
O
OH
H
H3C H
H
H3CO HO
H3C
H
HH3C
H
C=OOH
O
CH2OH
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Mineralocorticoid Horm.Mineralocorticoid Horm.• synthesized in the adrenal cortex• regulate blood pressure and volume by stimulating
the kidneys to absorb Na+, Cl-, and HCO3-
Aldosterone
C=O
CH2OH
O
H
H3C H
H
CHO
OH
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Bile AcidsBile Acids Synthesized in the liver, stored in the
gallbladder, and secreted into the intestine where their function is emulsify dietary fats and aid in their absorption and digestion
HO
H H
H
HOH
OH COOH
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Biosynthesis of SteroidsBiosynthesis of Steroids The building block from which all carbon atoms
of steroids are derived is the two carbon acetyl group of acetyl-CoAStage 1: synthesis of isopentenyl pyrophosphate from
three molecules of acetyl-CoA (Sect 19.4)
Stage 2: synthesis of cholesterol
Stage 3: conversion of cholesterol to other steroids
glucocorticoid hormones (e.g., cortisone)
mineralocorticoid hormones (e.g., aldosterone)
sex hormones (e.g., testosterone and estrone)
bile acids (e.g., cholic acid)
cholesterol
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CH3-C-S-CoAO
Acetyl Coenzyme A
Isopentenyl pyrophosphate
(R)-Mevalonate
(C10)
(C15)
Geranyl pyrophosphate
Farnesyl pyrophosphate
(C30) Squalene
C10 terpenes
C15 and C20 terpenes
C30 terpenes
OH
HO CH3O
-O
OP2O63-
Cholesterol
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PhospholipidsPhospholipids Phospholipids are the second most abundant
group of naturally occurring lipids• they are found almost exclusively in plant and animal
membranes, which typically consist of 40% -50% phospholipids and 50% - 60% proteins
• the most abundant phospholipids are derived from phosphatidic acid, a molecule in which glycerol is esterified with two molecules of fatty acid and one of phosphoric acid
• the three most abundant fatty acids in phosphatidic acids are palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1)
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PhospholipidsPhospholipids A phosphatidic acid
• further esterification with a low-molecular weight alcohol gives a phospholipid
• among the most common of these low-molecular-weight alcohols are
CH2
CH
CH2-O-P-O-
O
O
O
O glycerolpalmitic acid
stearic acidO
O-
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PhospholipidsPhospholipids• among the most common of these low-molecular-
weight alcohols are
Ethanolamine
+Choline Phosphatidylcholine
(Lecithin)
Phosphatidylethanolamine(Cephalin)
Serine Phosphatidylserine
Inositol Phosphatidylinositol
NH3+
HOHO
OHOH
OHHO
HOCH2CHCOO-
HOCH2CH2N(CH3)3
HOCH2CH2NH2
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PhospholipidsPhospholipids A lecithin
in aqueous solution, phospholipids spontaneously form into a lipid bilayer, with a back-to-back arrangement of lipid monolayers
CH2
CH
CH2
O
O
O
O
O P OCH2CH2N(CH3)3
O
O-
+
palmitic acid
stearic acid
glycerol
choline
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Biological MembranesBiological Membranes Fluid mosaic model:Fluid mosaic model: a biological membrane
consists of a phospholipid bilayer with proteins, carbohydrates, and other lipids embedded on the surface and in the bilayer• fluidfluid signifies that the protein components of
membranes “float” in the bilayer and can move freely along the plane of the membrane
• mosaicmosaic signifies that the various components of the membrane exist side by side, as discrete units rather than combining to form new molecules and ions
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Fat-Soluble VitaminsFat-Soluble Vitamins Vitamins are divided into two broad classes on
the basis of their solubility • those that are fat soluble, and hence classified as
lipids• those that are water soluble
The fat-soluble vitamins include A, D, E, and K
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Vitamin AVitamin A• occurs only in the animal world • found in the plant world in the form of a provitamin in
a group of pigments called carotenes
CH2OH
Retinol (Vitamin A)
cleavage of this C=C gives vitamin A
β-Carotene
- enzyme catalyzed cleavage and reduction in the liver
2
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Vitamin AVitamin A The best understood role of Vitamin A is its
participation in the visual cycle in rod cells• the active molecule is retinal (vitamin A aldehyde),
which forms an imine with an -NH2 group of the protein opsin to form the visual pigment called rhodopsin
• the primary chemical event of vision in rod cells is absorption of light by rhodopsin followed by isomerization of the 11-cis double bond to the 11-trans configuration
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Vitamin AVitamin A
CH=N-opsin11
12
CH=N-opsin
11
12
light
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Vitamin DVitamin D A group of structurally related compounds that
play a role in the regulation of calcium and phosphorus metabolism• the most abundant form in the circulatory system is
vitamin D3
Vitamin D3HO
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Vitamin EVitamin E Vitamin E is a group of compounds of similar
structure, the most active of which is α-tocopherol
• In the body, vitamin E functions as an antioxidant; it traps peroxy radicals of the type HOO• and ROO• formed as a result of oxidation by O2 of unsaturated hydrocarbon chains in membrane phospholipids
Four isoprene units, joined head-to-tail, beginning hereand ending at the aromatic ring
OH
O
Vitamin E (α- )Tocopherol
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Vitamin KVitamin K The name of this vitamin comes from the
German word Koagulation, signifying its important role in the blood-clotting process
Vitamin K1
isoprene units
2
O
O
O
OMenadione(a synthetic
vitamin K analog)
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Prob 26.12Prob 26.12Account for the detergent properties of each compound.
Pentaerythrityl palmitate(a neutral detergent)
Benzyldimethyloctylammonium chloride(a cationic detergent)
+CH3(CH2)6 CH2NCH3
HOCH2CCH2 OC(CH2)1 4CH3
Cl-
CH2C6H5
CH3
HOCH2
HOCH2
O
(a)
(b)
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Prob 26.15Prob 26.15Palmitic acid, CH3(CH2)14COOH, is used to prepare the hydrocarbon portions of these surface-acting germicides and fungicides. Show how to convert palmitic acid to 1-chlorohexadecane (cetyl chloride), and to N,N-dimethylhexadecanamine.
Benzylcetyldimethylammonium chloride
+
Cetylpyridinium chloride
+N
CH2(CH2)1 4CH3
CH2NCH2(CH2)1 4CH3
CH3
CH3
Cl-
Cl-
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Prob 26.16Prob 26.16Calculate the number of grams of epoxyalcohol that can be obtained from 100 g of racemic epoxyester by this stereospecific enzyme-catalyzed hydrolysis.
H2O, OH-O
O
O
O
O
O
HOHO
HThis enantiomer
is recovered unhydrolyzed
This epoxyalcohol is obtained in pure form
lipase
A racemic mixture
+ + -O
O
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Prob 26.18Prob 26.18Compare the structural formulas of unoprostone and PGF2α.
HO
HO O
CH3
COOH
HO
HO
COOH
HO H
Unoprostone(antiglaucoma)
PGF2α Stimulates contraction of
.uterine smooth muscle
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Prob 26.19Prob 26.19On this and the next two screens are the steps in the laboratory synthesis of doxaprost, an orally active bronchodilator. Propose reagents to bring about each step. Note that the bottom reactions on each screen are repeated at the top of the following screen.
(3)
(1) (2)
O
COOEtCOOEt
(CH2 )6COOCH3
O
O
(CH2 )6COOH
COOH
(4)(CH2 )6COOH
O
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Prob 26.19 (cont’d)Prob 26.19 (cont’d)• Doxoprost (reactions 3 and 4 are repeated here)
(3)
O
(CH2 )6COOH
COOH
(6)
(4)
(5)
(CH2 )6COOHO
O
(CH2 )6COOH
BrO
(CH2 )6COOH
(7)
Nefreaction
(8)
O
(CH2 )6COOCH3
CH2NO2
(CH2 )6COOCH3
O
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Prob 26.19 (cont’d)Prob 26.19 (cont’d)• Doxoprost
(7)
Nefreaction
(9)
(8)
O
(CH2 )6COOCH3
CH2NO2
(CH2 )6COOCH3
O
C=OH
(CH2 )6COOCH3
O
(11)
(10)
CCH3
C
CH
(CH2 )6COOCH3
O
C C
H
O
C (CH2 )4CH3
O
CH
C
(CH2 )4CH3
O(CH2 )6COOH
H H
(CH2 )6COOHO
CH
HO
(CH2 )4CH3
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Prob 26.24Prob 26.24Draw a stereorepresentation of cortisol showing the conformation of the five-membered ring and each six-membered ring.
C=OOH
CH2OH
H3C
H3C
H
H
H
O
HO
Cortisol(Hydrocortisone)
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Prob 26.25Prob 26.25Knowing what you do about the requirement for trans-coplanar ring opening of epoxide rings, draw the structural formula of the product formed by treating each epoxide with LiAlH4.
(b)(a)
H3C
CH3
H
HH
H3C
CH3
H
HH
O O
(d)(c)
H3C
CH3
H
HH
H3C
CH3
H
HHO O
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Prob 26.31Prob 26.31State the number of cis,trans isomers possible for vitamin A.
CH2OH
Retinol (Vitamin A)
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LipidsLipids
End Chapter 26End Chapter 26