1

Lipids

Building Bridges to Knowledge

Photo by Michaelle Cadet

Lipids may be classified as biological esters that are more soluble in organic solvents than water. Lipids represent a wide variety of structures including fatty acid esters of glycerol, steroids, sphingosine, and prostaglandins. Lipids are insoluble in water, but soluble in nonpolar organic solvents like carbon tetrachloride or diethyl ether. Fatty Acids Fatty acids are components of fats; therefore, they are referred to as fatty acids. Fatty acids are long chain carboxylic acids that contain an even number of carbon atoms. These fatty acids can be saturated or unsaturated.

2

Examples of saturated fatty acids are: Butyric acid, butanoic acid, CH3(CH2)2COOH Caproic acid, hexanoic acid, CH3(CH2)4COOH Caprylic acid, octanoic acid, CH3(CH2)6COOH Capric acid, decanoic acid, CH3(CH2)8COOH Lauric acid, dodecanoic acid, CH3(CH2)10COOH Myristic acid, tetradecanoic acid CH3(CH2)12COOH Palmitic acid, hexadodecanoic acid, CH3(CH2)14COOH Stearic acid, octadecanoic acid, CH3(CH2)16COOH Arachidic acid, eicosanoic acid, CH3(CH2)18COOH Examples of fatty acids with one double bond are:

(4Z)-decenoic acid

3

(9Z)-hexadecenoic acid

(6Z)-hexadecenoic acid

(9Z)-octadecenoic acid (oleic acid)

4

(11Z)-octadecenoic acid

(9Z)-eicosenoic acid Examples of fatty acids with multiple double bonds are:

(9Z,12Z)-octadecadienoic acid, linoleic acid

5

(9Z,12Z,15Z)-octadecatrienoic acid, linolenic acid

(5Z,8Z,11Z,14Z)-eicosatetraenoic acid, arachidonic acid Most naturally occurring fatty acids contain even numbers of carbon atoms combined with glycerol. Saturated fatty acids are solids that have high melting points due to their molecular structures. Saturated fatty acids have high melting points because their molecules are stackable and they have crystalline lattice structures. Unsaturated fatty aids are not stackable because of their centers of unsaturation; therefore, these systems have lower melting points than saturated fatty acids. In addition, unsaturated fatty acids are liquids at room temperature. Fats Fats are esters of long chain fatty acids and glycerol.

6

glycerol Fats, referred to as triglycerides, may be composed of the same fatty acid or mixed fatty acids. For example, tristearin or glyceryl tristearate is a triglyceride made up of stearic acid and glycerol.

tristearin Tripalmitan or glyceryl tripalmitate is a triglyceride made up of palmitic acid and glycerol.

7

Triolein or glyceryl trioleate or glyceryl (Z9)-octadecenoate is a triglyceride made up of oleic acid or (Z9)-octadecenoic acid and glycerol.

Naturally occurring fats contain fatty acids with mixed triglycerides. An example of a mixed triglyceride is glyceryl-1-oleate-2- stearate-3- palmitate, and the molecule would exhibit a chiral center on carbon atom number 2 of the glycerol fragment of the molecule; therefore, there are two possible stereoisomers for glyceryl-1-oleate-2- stearate-3- palmitate, the R and S designated isomers, glyceryl-1-oleate-2(R)- stearate-3- palmitate and glyceryl-1-oleate-2(S)- stearate-3- palmitate. Of the two, the mixed triglyceride with biological implications would be glyceryl-1-oleate-2(S)- stearate-3- palmitate.

8

glyceryl-1-oleate-2(S)- stearate-3- palmitate. Animal fats contain both saturated and unsaturated fats; however, saturated fats predominate in animals. Animal fats are generally solids at room temperature. Fats exist in warm blooded animals as a liquid. For example, fats in humans are liquids at 37oC. Hydrolysis is the most important reactions of fats.

Hydrolysis of fats can also occur in acidic medium.

9

When fats are heated the glycerol portion of the fat is converted into acrolein. Acrolein gives the odor to cooked meat.

glycerol acrolein Oils are liquid fats obtained from vegetable sources. They are structurally analogous to solid fats, but with unsaturated fatty acids. The iodine number measures the degree of unsaturation in fats. The iodine number is the number of grams of iodine that must be added to 100 grams of fat or oil. The more double bonds a fat contains, the greater the amount of iodine uptake required to react with the double bonds. Consequently, the higher the I2 number, the greater the degree of unsaturation in the fat or oil. http://en.wikipedia.org/wiki/Iodine_value lists a number of values for the iodine number of oils. For example, this site lists an iodine number of 80-88 for the olive oil, and 120-136 for soybean oil.

10

These values mean that soybean oil is composed of more unsaturated fatty acid than olive oil. Saturated fats and cholesterol are connected to arterial and coronary health issues, because these substances are deposited on arterial walls that calcify and harden the arteries. The arteries lose their elasticity creating arteriosclerosis. There is a significant correlation between ingestion of saturated fat and arteriosclerosis. Consequently, foods containing large amounts of saturated fats and cholesterol should be sparingly consumed. Fats containing unsaturated fatty acids rapidly deteriorate when exposed to water and oxygen. Fats are hydrolyzed by water to produce glycerol and unsaturated fatty acids, and the double bonds of unsaturated fatty acids are oxidized to a variety of aldehydes such as propandial. Soaps The alkali saponification of fats leads to the sodium salt of fatty acids. The sodium or potassium salts of fatty acids are called soaps. Sodium soaps are harder, and are cut into bars. Potassium salts of fatty acids are softer and generally are used as liquid soaps. A variety of fragrances and germicides are added to bar soaps and liquid soaps. Some soaps contain abrasives that give them scouring capabilities. Some soaps have the ability to float like ivory soap. These soaps contain a significant amount of added air before the hardening process. The mechanism of soap activity is described in the paper titled “Carboxylic Acids, Building Bridges to Knowledge.” Following is a general saponification reaction for the formation of soaps.

11

Soaps have a hydrophilic segment that dissolves in water and a hydrophobic segment that dissolves in oils, grease, and dirt. The carboxylate or hydrophilic segment of soaps causes the oils and dirt to be disperse throughout water. Waxes Waxes are moldable substances that easily harden when cooled. Waxes include a variety of substances such as paraffins, carbowax, and carnauba wax. Waxes are esters of long chain fatty acids and long chain alcohols. n-Hexatriacontanyl n-pentatriacontanoate is an example of a wax.

n-hexatriacontanyl n-pentatriacontanoate Natural waxes are mixtures of esters. Beeswax consists of esters with fatty acid fragments and alcohol fragments of 24-36 carbon atoms. Approximately 25% of beeswax consists of hydroxyacids, and 20% consists of hydrocarbons. In addition to high molecular mass esters, waxes contain hydrocarbons, esters of dicarboxylic acids, hydroxy acids, diols, or free alcohols. Nevertheless, waxes

12

have similar physical properties including appearance, feel to the touch, solubility, and melting points less than 100oC. Spermaceti, a wax found in the head cavity of sperm whales, primarily consists of n-hexadecanyl palmitate, often referred to as cetyl palmitate.

n-hexadecanyl palmitate n-Hexadecanyl palmitate in combination with other high molecular mass esters in spermaceti contribute to the broad melting point of the wax at about 40oC to 50oC. Spermaceti is useful is the cosmetic industry, lubricant making industry, in candle making industry, in the leather industry, and in the pharmaceutical industry. Since spermaceti is obtained from the head of whales, the whales must be destroyed. This is morally and environmentally unacceptable. An alternative to n-hexadecanyl palmitate is n-eicosanyl eicosanate.

n-eicosanyl eicosanate n-Eicosanyl eicosanate is chemically and physically similar to n-hexadecanyl palmitate. n-Eicosanyl eicosanate can be formed from jojoba oil. Phospholipids Phospholipids are esters of fatty acids and phosphoric acid. For example, phosphatides consist of glyceryl esters of fatty acids, phosphoric acid, and ethanolamine derivatives.

13

If R3 = H, then the phosphatides are called cephalins.

Cephalins Cephalins are found in brain tissue and nerves, and they are involved in clotting of blood. If R3 = CH3, then the phosphatides are referred to as lecithins

Lecithins Lecithins are constituents of nerve tissue and brain tissue. Lecithins are found in living organisms, and they are used in food as emulsifying agents. Some poisonous snakes have venom that

14

contain phospholipase enzymes that can hydrolyze one of the fatty acid esters of lecithin, and the resulting monodeesterified lecithin can cause the deterioration of red blood cells. Sphingolipids Sphingolipids contain a phosphoric acid unit and sphingosine in the place of glycerol as the alcohol. In addition, sphingolipids contain unsaturated fatty acid. The simplest sphingolipid is sphingomyelin.

sphingomyelin The red portion of sphingomyelin is sphingosine, the blue portion is oleic acid, (9Z)-octadecenoic acid, the black portion is phosphoric acid, and the green portion is choline. Sphingomyelin has two chiral atoms. Chiral carbon atom labeled 1 has an “S” designation and the chiral carbon atom labeled 2 has an “R” designation. Sphingomyelin is an important constituent of myelin sheath that surrounds the long slender projection of nerve cells (neurons) called axons. Axons, nerve fibers, conduct electrical impulses away from the neurons; therefore, removing or stripping myelin sheaths from axons may result in an interruption of the ability of electrical impulses moving away from cellular neurons. The interruption of the conductivity of electrical impulses could lead to multiple sclerosis.

15

Glycolipids Glycolipids may contain glycerol, sphingosine, fatty acids and carbohydrates. The simplest glycolipids contain two fatty acids and a monosaccharide. An example of a simple glycolipid is one containing D-galactose, and the esters of two stearic acid molecules.

a glycolipid The second carbon atom in this simple glycolipid is chiral, and its designation is “R.” Glycolipids occur in microorganisms and in plants. Cerebrosides are another group of glycolipids containing D-galactose, fatty acids, and spingosine.

a cerebroside

16

Cerebrosides can also be classified as sphingolipids, and they are constituents of nerve cells and brain cells. If glucose is substituted for galactose in the cerebroside, then the spleen and liver would be enlarged.

Cerebrosides accumulate in the phagocytic cells that attack foreign antigens that invade biosystems. Gangliosides, similar to cerebrosides, are very important as imunogenic agents. Gangliosides consist of glycosphingolipids, sialic acid, and monosaccharides. Gangliosides are components of cell plasma membrane, and gangliosides regulate communicating signals between cells.

a ganglioside The green portion represents sialic acid, N-acetylneuraminic acid, and the black portion is glucose, a monsaccharide. In addition, gangliosides release proteins that regulate survival.

17

Steroids Gangliosides, cerebrosides, waxes, and fats are saponifiable. However, steroids will not react with NaOH or KOH, because steroids are esters. Examples of steroids are cholesterol, testosterone, estrone, cortisone, and the bile salts. The basic skeletal structure of steroids is the cyclopentanoperhydrophenanthrene nucleus.

cyclopentanoperhydrophenanthrene nucleus The most familiar steroid is cholesterol.

cholesterol Cholesterol is a component of animal systems. Ten percent of the brain consists of cholesterol. Cholesterol is found as a component in gallstones. Sodium Cholate and sodium deoxycholate are steroids salts that participate in the digestive system. They are traditionally referred to as bile salts, and they assist in the digestion of fats. Sodium cholate and sodium deoxycholate are the primary chemicals of bile. The bile salts function as biological soaps and emulsifying agents. They break fats into smaller fragments and suspend them in aqueous solution. The emulsified fats can be more easily transported by digestive mechanisms.

18

sodium cholate sodium deoxycholate Prostaglandins Prostaglandins originate from fatty acids with twenty carbon atoms such as (8Z, 11Z, 14Z)-eicosanoic acid.

(8Z, 11Z, 14Z)-eicosanoic acid The syntheses of the six primary prostaglandins from eicosanoic acid may be represented by viewing the following pathway for the synthesis of prostglandin E1 from (8Z, 11Z, 14Z)-eicosanoic acid.

19

Primary prostaglandins are present in small quantities within the biological systems, and they are powerful natural chemicals.

20

Prostaglandins regulate the contraction and relaxation of smooth muscle activity, and though they act like hormones, they are not hormones since they are not produced at discrete sites in the body. Prostaglandins can be used to treat ulcers, hypertension, emphysema, male sterility, and they can be used to induce labor. Following is a structure of another prostaglandins, prostaglandin F2α.

Prostaglandin F2α Prostaglandin F2α is a naturally occurring prostaglandin used to induce labor. Prostaglandin F2α is produced by the uterus when stimulated by oxytocin. It acts on the corpus luteum resulting in ovary scarring and inhibiting the production of progesterone. The corpus luteum is involved in the production of progesterone and estradiol. The function of prostaglandin F2α is dependent on the number of receptors on the corpus luteum membrane. Cell Membranes An interesting discussion on cell membrane can be found at the following website: http://library.thinkquest.org/C004535/cell_membranes.html

21

Problems Lipids

1. Suggest chemical structures for compounds 1 through VIII in the following reaction schema that results in the synthesis of an important biologically active lipid.

(1)

(2)

(3)

22

(4)

(5)

(6)

(7)

23

(8)

2. The following 1HNMR spectra represent compounds A and B.

Both compounds have identical molecular formulas C18H36O2. Based on the proton magnetic spectroscopy data, suggest structural formulas for compound A and compound B.

1HNMR of Compound A

1HNMR of Compound B

24

3. A study of a naturally occurring fatty acid (C18H34O2) found in

ruminants and dairy products suggests that the fatty acid has the potential to lower low density lipoproteins in rats. The laboratory synthesis of C18H34O2 can be accomplished using the following steps.

(1)

(2)

(3)

25

(4)

(5)

(6)

Suggest structures for C8H14, C8H13Na , Compound A, C18H31N, and C18H34O2 4. An unknown wax, isolated from whales, exhibits physical properties analogous to high molecular mass hydrocarbons. For example, the wax does not react with bromine in carbon tetrachloride, and It does not react with dilute potassium permanganate. The infrared spectrum of the wax exhibits characteristic transmittance bands at 1752 cm-1, 1250 cm-1, and 1055 cm-1. The wax is refluxed in NaOH in ethanol over an extended period of time, followed by separation in a separator funnel (using several water/ether mixtures). The aqueous layer, after acidification, gives a neutralization equivalence of 258 ±2, and melts between 62oC and 63oC. The ether layer, after evaporation, gives a solid that melts between 48oC and 49oC. Reduction (with LiAlH4) of the solid (obtained from the acidified aqueous layer) gives a solid with a melting point between 48oC and 49oC. Suggest a chemical structure for this unknown wax.

26

5. Saponification of a lipid (isolated from the cerebellum) produces an acid that decolorizes dilute potassium permanganate and bromine in carbon tetrachloride. Catalytic hydrogenation of the acid produces compound A. Oxidation (with hot potassium permanganate in sodium hydroxide) of the saponified and acidified lipid, followed by acidification, produced two acids. One acid has a neutralization equivalent of 156±3, and the other acid has a neutralization equivalence of 137±2.

Compound A Suggest a structure for the acid produced from the saponification of the cerebellum lipid, and the two acids produced by the vigorous oxidation of the acid produced from the saponification of the cerebellum lipid.

27

Solutions to Lipid Problems 1. (1)

28

(2)

(3)

29

(4)

(5)

30

(6)

31

(7)

32

(8)

2. The following 1HNMR spectra represent compounds A and B.

Both compounds have identical molecular formulas C18H36O2. Based on the proton magnetic spectroscopy data, suggest structural formulas for compound A and compound B.

33

1HNMR of Compound A

34

1HNMR of Compound B

35

3. (1)

(2)

36

(3)

37

(4)

(5)

38

39

(6)

4. An unknown wax, isolated from whales, exhibits physical properties analogous to high molecular mass hydrocarbons. For example, the wax does not react with bromine in carbon tetrachloride, and It does not react with dilute potassium permanganate. The infrared spectrum of the wax exhibits characteristic transmittance bands at 1752 cm-1, 1250 cm-1, and 1055 cm-1.

40

The wax is refluxed in NaOH in ethanol over an extended period of time, followed by separation in a separator funnel (using several water/ether mixtures). The aqueous layer, after acidification, gives a neutralization equivalence of 258±2, and melts between 62oC and 63oC. The ether layer, after evaporation, gives a solid that melts between 48oC and 49oC. Reduction (with LiAlH4) of the solid (obtained from the acidified aqueous layer) gives a solid with a melting point between 48oC and 49oC. Suggest a chemical structure for this unknown wax.

5. Saponification of a lipid (isolated from the cerebellum) produces an acid that decolorizes dilute potassium permanganate and bromine in carbon tetrachloride. Catalytic hydrogenation of the acid produces compound A. Oxidation (with hot potassium permanganate in sodium hydroxide) of the saponified and acidified lipid, followed by acidification, produced two acids. One acid has a neutralization equivalent of 156±3, and the other acid has a neutralization equivalence of 137±2.

Compound A Suggest a structure for the acid produced from the saponification of the cerebellum lipid, and the two acids produced by the vigorous oxidation of the acid produced from the saponification of the cerebellum lipid.

41

Acid produced from the saponification of the cerebellum lipid

MW = 272 g/mol MW = 158 g/mol Neutralization Equivalent = 136 Neutralization Equivalent = 158