LIPIDS OR FATS

Lipids

The lipids are a large and diverse group of naturally occuring organic compounds that are related by their solubility in nonpolar organic solvents (e.g. ether, chloroform, acetone & benzene) and general insolubility in water. There is great structural variety among the lipids, as will be demonstrated in the following sections.

Fatty Acids
Soaps and Detergents
Fats and Oils
Waxes
Phospholipids
Eicosonoids
Terpenes
Steroids
Lipid Soluble Vitamins

Fatty Acid Derivatives

Fats, Oils, Waxes & Phospholipids

1. Fatty Acids

The common feature of these lipids is that they are all esters of moderate to long chain fatty acids. Acid or base-cayalyzed hydrolysis yields the component fatty acid, some examples of which are given in the following table, together with the alcohol component of the lipid. These long-chain carboxylic acids are generally referred to by their common names, which in most cases reflect their sources. Natural fatty acids may be saturated or unsaturated, and as the following data indicate, the saturated acids have higher melting points than unsaturated acids of corresponding size. The double bonds in the unsaturated compounds listed on the right are all cis (or Z).

FATTY ACIDS
Saturated Formula Common Name Melting Point CH3(CH2)10CO2H lauric acid 45° C CH3(CH2)12CO2H myristic acid 55° C CH3(CH2)14CO2H palmitic acid 63° C CH3(CH2)16CO2H stearic acid 69° C CH3(CH2)18CO2H arachidic acid 76° C

Unsaturated
Formula	Common Name	Melting Point
CH3(CH2)5CH=CH(CH2)7CO2H	palmitoleic acid	0° C
CH3(CH2)7CH=CH(CH2)7CO2H	oleic acid	13° C
CH3(CH2)4CH=CHCH2CH=CH(CH2)7CO2H	linoleic acid	-5° C
CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CO2H	linolenic acid	-11° C
CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CO2H	arachidonic acid	-49° C

The higher melting points of the saturated fatty acids reflect the uniform rod-like shape of their molecules. The cis-double bond(s) in the unsaturated fatty acids introduce a kink in their shape, which makes it more difficut to pack their molecules together in a stable repeating array or crystalline lattice. The trans-double bond isomer of oleic acid, known as elaidic acid, has a linear shape and a melting point of 45° C (32° C higher than its cis isomer). The shapes of stearic and oleic acids are displayed in the models below. You may examine Chime models of these compounds by clicking on the desired model picture.

stearic acid		oleic acid

Two polyunsaturated fatty acids, linoleic and linolenic, are designated "essential" because their absence in the human diet has been associated with health problems, such as scaley skin, stunted growth and increased dehydration. These acids are also precursors to the prostaglandins, a family of physiologically potent lipids present in minute amounts in most body tissues.
Because of their enhanced acidity, carboxylic acids react with bases to form ionic salts, as shown in the following equations. In the case of alkali metal hydroxides and simple amines (or ammonia) the resulting salts have pronounced ionic character and are usually soluble in water. Heavy metals such as silver, mercury and lead form salts having more covalent character (3rd example), and the water solubility is reduced, especially for acids composed of four or more carbon atoms.

RCO2H	+	NaHCO3		RCO2(-) Na(+)   +   CO2   +   H2O
RCO2H	+	(CH3)3N:		RCO2(-) (CH3)3NH(+)
RCO2H	+	AgOH		RCO2d(-) Agd(+)   +   H2O

2. Soaps and Detergents

Carboxylic acids and salts having alkyl chains longer than eight carbons exhibit unusual behavior in water due to the presence of both hydrophilic (CO₂) and hydrophobic (alkyl) regions in the same molecule. Such molecules are termed amphiphilic (Gk. amphi = both) or amphipathic. Fatty acids made up of ten or more carbon atoms are nearly insoluble in water, and because of their lower density, float on the surface when mixed with water. Unlike paraffin or other alkanes, which tend to puddle on the waters surface, these fatty acids spread evenly over an extended water surface, eventially forming a monomolecular layer in which the polar carboxyl groups are hydrogen bonded at the water interface, and the hydrocarbon chains are aligned together away from the water. This behavior is illustrated in the diagram on the right. Substances that accumulate at water surfaces and change the surface properties are called surfactants.

Alkali metal salts of fatty acids are more soluble in water than the acids themselves, and the amphiphilic character of these substances also make them strong surfactants. The most common examples of such compounds are soaps and detergents, four of which are shown below. Note that each of these molecules has a nonpolar hydrocarbon chain, the "tail", and a polar (often ionic) "head group". The use of such compounds as cleaning agents is facilitated by their surfactant character, which lowers the surface tension of water, allowing it to penetrate and wet a variety of materials.

Very small amounts of these surfactants dissolve in water to give a random dispersion of solute molecules. However, when the concentration is increased an interesting change occurs. The surfactant molecules reversibly assemble into polymolecular aggregates called micelles. By gathering the hydrophobic chains together in the center of the micelle, disruption of the hydrogen bonded structure of liquid water is minimized, and the polar head groups extend into the surrounding water where they participate in hydrogen bonding. These micelles are often spherical in shape, but may also assume cylindrical and branched forms, as illustrated on the right. Here the polar head group is designated by a blue circle, and the nonpolar tail is a zig-zag black line.

An animated display of micelle formation is presented below. Notice the brownish material in the center of the three-dimensional drawing on the left. This illustrates a second important factor contributing to the use of these amphiphiles as cleaning agents. Micelles are able to encapsulate nonpolar substances such as grease within their hydrophobic center, and thus solubilize it so it is removed with the wash water. Since the micelles of anionic amphiphiles have a negatively charged surface, they repel one another and the nonpolar dirt is effectively emulsified. To summarize, the presence of a soap or a detergent in water facilitates the wetting of all parts of the object to be cleaned, and removes water-insoluble dirt by incorporation in micelles. If the animation has stopped, it may be restarted by clicking on it.

The oldest amphiphilic cleaning agent known to humans is soap. Soap is manufactured by the base-catalyzed hydrolysis (saponification) of animal fat (see below). Before sodium hydroxide was commercially available, a boiling solution of potassium carbonate leached from wood ashes was used. Soft potassium soaps were then converted to the harder sodium soaps by washing with salt solution. The importance of soap to human civilization is documented by history, but some problems associated with its use have been recognized. One of these is caused by the weak acidity (pK_a ca. 4.9) of the fatty acids. Solutions of alkali metal soaps are slightly alkaline (pH 8 to 9) due to hydrolysis. If the pH of a soap solution is lowered by acidic contaminants, insoluble fatty acids precipitate and form a scum. A second problem is caused by the presence of calcium and magnesium salts in the water supply (hard water). These divalent cations cause aggregation of the micelles, which then deposit as a dirty scum.
These problems have been alleviated by the development of synthetic amphiphiles called detergents (or syndets). By using a much stronger acid for the polar head group, water solutions of the amphiphile are less sensitive to pH changes. Also the sulfonate functions used for virtually all anionic detergents confer greater solubility on micelles incorporating the alkaline earth cations found in hard water. Variations on the amphiphile theme have led to the development of other classes, such as the cationic and nonionic detergents shown above. Cationic detergents often exhibit germicidal properties, and their ability to change surface pH has made them useful as fabric softners and hair conditioners. These versatile chemical "tools" have dramatically transformed the household and personal care cleaning product markets over the past fifty years.

3. Fats and Oils

The triesters of fatty acids with glycerol (1,2,3-trihydroxypropane) compose the class of lipids known as fats and oils. These triglycerides (or triacylglycerols) are found in both plants and animals, and compose one of the major food groups of our diet. Triglycerides that are solid or semisolid at room temperature are classified as fats, and occur predominantly in animals. Those triglycerides that are liquid are called oils and originate chiefly in plants, although triglycerides from fish are also largely oils. Some examples of the composition of triglycerides from various sources are given in the following table.

	Saturated Acids (%)					Unsaturated Acids (%)
Source	C10 & less	C12 lauric	C14 myristic	C16 palmitic	C18 stearic	C18 oleic	C18 linoleic	C18 unsaturated
Animal Fats
butter	15	2	11	30	9	27	4	1
lard	-	-	1	27	15	48	6	2
human fat	-	1	3	25	8	46	10	3
herring oil	-	-	7	12	1	2	20	52
Plant Oils
coconut	-	50	18	8	2	6	1	-
corn	-	-	1	10	3	50	34	-
olive	-	-	-	7	2	85	5	-
palm	-	-	2	41	5	43	7	-
peanut	-	-	-	8	3	56	26	7
safflower	-	-	-	3	3	19	76	-

As might be expected from the properties of the fatty acids, fats have a predominance of saturated fatty acids, and oils are composed largely of unsaturated acids. Thus, the melting points of triglycerides reflect their composition, as shown by the following examples. Natural mixed triglycerides have somewhat lower melting points, the melting point of lard being near 30° C, whereas olive oil melts near -6° C. Since fats are valued over oils by some Northern European and North American populations, vegetable oils are extensively converted to solid triglycerides (e.g. Crisco) by partial hydrogenation of their unsaturated components. Some of the remaining double bonds are isomerized (to trans) in this operation. These saturated and trans-fatty acid glycerides in the diet have been linked to long-term health issues such as atherosclerosis.

Triglycerides having three identical acyl chains, such as tristearin and triolein (above), are called "simple", while those composed of different acyl chains are called "mixed". If the acyl chains at the end hydroxyl groups (1 & 3) of glycerol are different, the center carbon becomes a chiral center and enantiomeric configurations must be recognized.

The hydrogenation of vegetable oils to produce semisolid products has had unintended consequences. Although the hydrogenation imparts desirable features such as spreadability, texture, "mouth feel," and increased shelf life to naturally liquid vegetable oils, it introduces some serious health problems. These occur when the cis-double bonds in the fatty acid chains are not completely saturated in the hydrogenation process. The catalysts used to effect the addition of hydrogen isomerize the remaining double bonds to their trans configuration. These unnatural trans-fats appear to to be associated with increased heart disease, cancer, diabetes and obesity, as well as immune response and reproductive problems.

 

4. Waxes

Waxes are esters of fatty acids with long chain monohydric alcohols (one hydroxyl group). Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. The formulas for three well known waxes are given below, with the carboxylic acid moiety colored red and the alcohol colored blue.

spermaceti		beeswax		carnuba wax
CH3(CH2)14CO2-(CH2)15CH3		CH3(CH2)24CO2-(CH2)29CH3		CH3(CH2)30CO2-(CH2)33CH3

Waxes are widely distributed in nature. The leaves and fruits of many plants have waxy coatings, which may protect them from dehydration and small predators. The feathers of birds and the fur of some animals have similar coatings which serve as a water repellent. Carnuba wax is valued for its toughness and water resistance.

5. Phospholipids

Phospholipids are the main constituents of cell membranes. They resemble the triglycerides in being ester or amide derivatives of glycerol or sphingosine with fatty acids and phosphoric acid. The phosphate moiety of the resulting phosphatidic acid is further esterified with ethanolamine, choline or serine in the phospholipid itself. The following diagram shows the structures of some of these components. Clicking on the diagram will change it to display structures for two representative phospholipids. Note that the fatty acid components (R & R') may be saturated or unsaturated. To see a Chime model of a phospholipid Click Here.

As ionic amphiphiles, phospholipids aggregate or self-assemble when mixed with water, but in a different manner than the soaps and detergents. Because of the two pendant alkyl chains present in phospholipids and the unusual mixed charges in their head groups, micelle formation is unfavorable relative to a bilayer structure. If a phospholipid is smeared over a small hole in a thin piece of plastic immersed in water, a stable planar bilayer of phospholipid molecules is created at the hole. As shown in the following diagram, the polar head groups on the faces of the bilayer contact water, and the hydrophobic alkyl chains form a nonpolar interior. The phospholipid molecules can move about in their half the bilayer, but there is a significant energy barrier preventing migration to the other side of the bilayer. To see an enlarged segment of a phospholipid bilayer Click Here.
This bilayer membrane structure is also found in aggregate structures called liposomes. Liposomes are microscopic vesicles consisting of an aqueous core enclosed in one or more phospholipid layers. They are formed when phospholipids are vigorously mixed with water. Unlike micelles, liposomes have both aqueous interiors and exteriors.

A cell might be considered a very complex liposome. The bilayer membrane that separates the interior of a cell from the surrounding fluids is largely composed of phospholipids, but it incorporates many other components that contribute to its structural integrity and permit the transport of various kinds of chemical species in and out of the cell. The interior of a cell contains a variety of structures (organelles) that conduct chemical operations vital to the cells existence. Molecules bonded to the surfaces of cells serve to identify specific cells and facilitate interaction with external chemicals.
The sphingomyelins are also membrane lipids. They are the major component of the myelin sheath surrounding nerve fibers. Multiple Sclerosis is a devastating disease in which the myelin sheath is lost, causing eventual paralysis.

Steroids

The important class of lipids called steroids are actually metabolic derivatives of terpenes, but they are customarily treated as a separate group. Steroids may be recognized by their tetracyclic skeleton, consisting of three fused six-membered and one five-membered ring, as shown in the diagram to the right. The four rings are designated A, B, C & D as noted, and the peculiar numbering of the ring carbon atoms (shown in red) is the result of an earlier misassignment of the structure. The substituents designated by R are often alkyl groups, but may also have functionality. The R group at the A:B ring fusion is most commonly methyl or hydrogen, that at the C:D fusion is usually methyl. The substituent at C-17 varies considerably, and is usually larger than methyl if it is not a functional group. The most common locations of functional groups are C-3, C-4, C-7, C-11, C-12 & C-17. Ring A is sometimes aromatic. Since a number of tetracyclic triterpenes also have this tetracyclic structure, it cannot be considered a unique identifier.
Steroids are widely distributed in animals, where they are associated with a number of physiological processes. Examples of some important steroids are shown in the following diagram. Different kinds of steroids will be displayed by clicking the "Toggle Structures" button under the diagram. Norethindrone is a synthetic steroid, all the other examples occur naturally. A common strategy in pharmaceutical chemistry is to take a natural compound, having certain desired biological properties together with undesired side effects, and to modify its structure to enhance the desired characteristics and diminish the undesired. This is sometimes accomplished by trial and error.
The generic steroid structure drawn above has seven chiral stereocenters (carbons 5, 8, 9, 10, 13, 14 & 17), which means that it may have as many as 128 stereoisomers. With the exception of C-5, natural steroids generally have a single common configuration. This is shown in the last of the toggled displays, along with the preferred conformations of the rings.

Chemical studies of the steroids were very important to our present understanding of the configurations and conformations of six-membered rings. Substituent groups at different sites on the tetracyclic skeleton will have axial or equatorial orientations that are fixed because of the rigid structure of the trans-fused rings. This fixed orientation influences chemical reactivity, largely due to the greater steric hindrance of axial groups versus their equatorial isomers. Thus an equatorial hydroxyl group is esterified more rapidly than its axial isomer.
To see a Chime model of the steroid cholesterol Click Here.
It is instructive to examine a simple bicyclic system as a model for the fused rings of the steroid molecule. Decalin, short for decahydronaphthalene, exists as cis and trans isomers at the ring fusion carbon atoms. Planar representations of these isomers are drawn at the top of the following diagram, with corresponding conformational formulas displayed underneath. The numbering shown for the ring carbons follows IUPAC rules, and is different from the unusual numbering used for steroids. For purposes of discussion, the left ring is labeled A (colored blue) and the right ring B (colored red). In the conformational drawings the ring fusion and the angular hydrogens are black.

The trans-isomer is the easiest to describe because the fusion of the A & B rings creates a rigid, roughly planar, structure made up of two chair conformations. Each chair is fused to the other by equatorial bonds, leaving the angular hydrogens (H^a) axial to both rings. Note that the bonds directed above the plane of the two rings alternate from axial to equatorial and back if we proceed around the rings from C-1 to C-10 in numerical order. The bonds directed below the rings also alternate in a complementary fashion.
Conformational descriptions of cis- decalin are complicated by the fact that two energetically equivalent fusions of chair cyclohexanes are possible, and are in rapid equilibrium as the rings flip from one chair conformation to the other. In each of these all chair conformations the rings are fused by one axial and one equatorial bond, and the overall structure is bent at the ring fusion. In the conformer on the left, the red ring (B) is attached to the blue ring (A) by an axial bond to C-1 and an equatorial bond to C-6 (these terms refer to ring A substituents). In the conformer on the right, the carbon bond to C-1 is equatorial and the bond to C-6 is axial. Each of the angular hydrogens (H^ae or H^ea) is oriented axial to one of the rings and equatorial to the other. This relationship reverses when double ring flipping converts one cis-conformer into the other.
Cis-decalin is less stable than trans-decalin by about 2.7 kcal/mol (from heats of combustion and heats of isomerization data). This is due to steric crowding (hindrance) of the axial hydrogens in the concave region of both cis-conformers, as may be seen in the Chime display activated by the following button. This difference is roughly three times the energy of a gauche butane conformer relative to its anti conformer. Indeed three gauche butane interactions may be identified in each of the cis-decalin conformations, as will be displayed by clicking on the above conformational diagram. These gauche interactions are also shown in the Chime model.
To see Chime models of cis & trans-decalin

Steroids in which rings A and B are fused cis, such as the example on the right, do not have the same conformational mobility exhibited by cis-decalin. The fusion of ring C to ring B in a trans configuration prevents ring B from undergoing a conformational flip to another chair form. If this were to occur, ring C would have to be attached to ring B by two adjacent axial bonds directed 180° apart. This is too great a distance to be bridged by the four carbon atoms making up ring C. Consequently, the steroid molecule is locked in the all chair conformation shown here. Of course, all these steroids and decalins may have one or more six-membered rings in a boat conformation. However the high energy of boat conformers relative to chairs would make such structures minor components in the overall ensemble of conformations available to these molecules.