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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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26-5

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