Lipids

Introduction.

Lipids are a diverse class of naturally occurring molecules which have in common essentially only the method of their isolation, which is by extraction of cells or tissues with a nonpolar organic solvent. They are therefore relatively nonpolar themselves. Our discussions will center upon two main sub-groups of lipids: (1) triglycerides and (2) terpenes and steroids.

Triglycerides

Triglycerides arenaturally occurring tri-esters of 1,2,3-propanetriol (glycerol; also called glycerin). The carboxylic acid portion of the ester is typically derived from a long chain carboxylic acid, such as stearic acid and palmitic acid.

The generalized structure of triglycerides is therefore as shown below:

q In most cases, the carboxylic acids found in triglycerides have from 10-20 carbons in the chain.

q The number of carbons in the chain is virtually always an even number. We shall see why this is a little later.

q The R groups may be the same or different.

Unsaturated Acids

Although the carbon chains in many of the carboxylic acids found in triglycerides are saturated (except for the carbon of the carboxyl function), many unsaturated acids are found, also. In fact there may be one, two, three, or even more C=C bonds in the chain. Two examples of the unsaturated acids which are commonly found in triglycerides are given below:

q Note that in most triglycerides, the C=C’s have the thermodynamically less stable cis geometry.

q When two or more C=C’s are present, they are non-conjugated.

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Fats and Oils.

Naturally occurring triglycerides may be either solid or liquid at room temperature. Commonly, solid triglycerides are called fats and liquid triglycerides are called oils. The carboxylic acid moieties involved in forming fats and oils are often referred to as fatty acids (even numbered, C12-C18 mostly).

q Triglycerides which have all or most of their acidic moieties saturated are most often solid.

q These solid triglycerides or fats are most often found in animal triglycerides.

q Triglycerides which have most of their acidic moieties unsaturated are more often liquids.

q These are referred to as oils, and they are more commonly found in plant triglycerides.

q There are exceptions to these generalities, e.g., some plants have large amounts of saturated triglycerides.

q A simple explanation of why unsaturated triglycerides have lower m.p.’s (i.e., are liquid at room temperature) is found in the ease of packing of the respective molecules into a snug crystal lattice.

q The all anti saturated alkane linkages fit together nicely and provide close approach and favorable van der Waals attractive forces.

q The cis double bonds hinder close approach and diminish the van der Waals interactions (see dotted lines for repulsions which impede close approach of the rest of the chain. They also prevent the formation of extended, linear lattice.

q Interestingly, unsaturated triglycerides which have trans double bonds tend to have higher m.p.’s than the ones with cis double bonds, and thus to be solid at room temperature. They, like the saturated analogues, tend to pack densely into a rather linear, extended lattice.

Hydrolysis of Triglycerides

Since triglycerides are esters, they are readily hydrolyzed via either acid catalysis or base promotion. Base promoted hydrolysis is of special importance and will be considered exclusively here.

q When 3 moles of hydroxide ion are used to hydrolyse a mole of triglyceride in aqueous solution, the products are one mole of glycerol and three moles of sodium salts of the carboxylic acids which were present in bound form in the triglyceride.

q Acidic aqueous workup gives the carboxylic acids, themselves. These naturally occurring acids are often called “fatty acids”.

q Since fats and oils are available in abundance, this hydrolysis can be used to produce glycerol and either the sodium salts of carboxylic acids or the fatty acids, themselves.

q The sodium salts are especially useful because they constitute “soap”.

Soaps

Soaps exert their cleansing action in aqueous solution because of the formation of fundamental particles called micelles.

q An illustration of the structure of a soap micelle is shown below. Note that the interior of the micelle is nonpolar because it contains all of the nonpolar hydrocarbon “tails” of the soap.

q The exterior of the micelle is highly polar because it contains all of the ions: the negative carboxylate ions and the sodium ions. These are nicely solvated and stabilized by the surrounding solvent molecules. The nonpolar “tails” are protected from the water, which which they would not interact favorably.

q The hydrocarbon tails interact with each other favorably by van der Waals attractions.

q The result is that nonpolar substances like grease are able to enter the interior of the micelle and be favorably solvated by the nonpolar tails. In this way, substances which would not dissolve in water at all, are able to be included inside the aqueous phase.

q Note that micelles are not considered to be dissolved in the ordinary sense, because they are rather large particles, but neither are they considered to be suspended particles. They are intermediate species. Typically, micelles might contain 50-200 molecules in a roughly spherical shape.

q It turns out, interestingly, that the length of the hydrocarbon tails which are present in naturally occurring fatty acids, are just right for forming stable micelles, which are essential to cleansing action.

q If the fatty acid salt has less than 12 carbons, the van der Waals attractions between the tails is not large enough to afford a stable interior for the micelle. If it is more than about 18 carbons, the van der Waals interactions are too strong, and they result in precipitation of the salt, with the tails interacting more strongly in the solid, insoluble lattice.

q Potassium salts can also be used. They tend to be softer solids (or even liquids) than sodium salts.

Detergents

q The basic principle behind the cleansing action of soap is the ability to form micelles with a nonpolar interior.

q This merely requires molecules which have a highly polar part and a nonpolar part. Of course, the nonpolar part must have a length and shape which will permit the formation of a stable micelle.

q For example, the ionic part could be an anion other than a carboxylate anion. Synthetic cleansers, known as detergents, have been synthesized which use the sulfonate anion as the ionic part.

q By doing this, it has been found that sulfonate based detergents are compatible with “hard water” (i.e., water which contains dissolved calcium and magnesium ions), whereas soap is not.

q In the presence of either of these ions, soap exchanges its counterion and precipitates out of solution as the insoluble calcium or magnesium salt of the fatty acid. However, the sulfonate salts of calcium and magnesium are soluble, so these ions do not interfere with micelle formation.

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q See if you can devise an efficient commercial synthesis of the detergent shown above, starting with benzene and using the typical electrophilic aromatic substitution reactions which we studied earlier in the semester. [How do you install an alkyl group? A sulfonic acid moiety? Which should go first, alkylation or sulfonation?]

Terpenes and Steroids

Terpenes are naturally occurring organic compounds which are ultimately formed from acetyl coenzme A via isopentenyl pyrophosphate, the structure of which is shown below.

q Since isopentenyl pyrophosphate is the ultimate source of all the carbon atoms in terpenes, they typically have a total number of carbon atoms which is divisible by five.

q The simplest terpenes (we can call them monoterpenes), therefore have 10 carbon atoms. The next higher series have 15 carbons . These are called sesquiterpenes (these have 1.5 terpene units). The next groups has 20 carbons and are called diterpenes. Terpenes which have 30 carbons are called triterpenes.

q The mechanism for the formation of the basic terpene building block is shown below. The starting point is isopentenyl pyrophosphate. A molecule of this reactant is first isomerized (the disubstituted double bond is isomerized into a more stable trisubstituted double bond; detailed mechanism not given here).

q At this point the pyrophosphate moiety, which is a good leaving group, is allylic and reactive. In an S_N substitution, the double bond of a molecule of isopentenylpyrophosphate acts as a nucleophile (at its unhindered terminal carbon) to displace the pyrophosphate moiety from the allylic position, and generate a carbon-carbon bond which links the two molecules, forming a ten carbon pyrophosphate.

q The 10 carbon molecule is called geranyl pyrophosphate. This molecule is considered to be the key intermediate for the formation of all monoterpenes, and by further reaction with another molecule of isopentenylpyrophosphate, as a precursor for forming sequiterpenes and diterpenes. We will discuss the mechanism of formation of triterpenes further along.

q We might note that the pyrophosphate anion (P₂O₆^-4 ) is generally considered to be nature’s choice of leaving group.

THE ISOMERIZATION STEP

THE CARB0N-CARBON BOND FORMING STEPS

q As was noted above, geranyl pyrophosphate is considered to be the precursor for all monoterpenes. An example of the formation of limonene, an essential oil present in lemons, is shown below.

q It was noted above, also, that the C15 pyrophosphate, farnesyl pyrophosphate, is the direct precursor of all sesquiterpenes.

q Incidentally, the triterpenes, which are closely related to the steroids, are not formed by continuing to add isopentenyl pyrophosphate molecules one at a time. Instead, two farnesyl pyrophosphate molecules are coupled together to give a C30 molecule which is the precursor of triterpenes and steroids. This molecule is called squalene.

q The structure of squalene is given below, but the biochemical mechanism for its formation is not covered here.

STEROIDS

The polyunsaturated molecule squalene undergoes a unique and impressive cyclization reaction which leads to polyclic triterpenes and steroids. We will not examine this mechanism in detail, although it has been elegantly worked out, especially by Professor E.J. Corey (Harvard), but it is a carbocation mechanism not unlike we have seen for the formation of limonene, except that several rings are formed consecutively.

q Steroids are naturally occurring molecules which typically have the tetracyclic polycyclic skeleton shown below. It may be noted that cholesterol and other steroids do not have 30 carbon atoms; they have lost a few, but they are derived biochemically from the triterpenes. Also, steroids have additional functionalities which triterpenes lack.

Cholesterol

A conformational structure which better reveals the specific conformation and configuration of cholesterol is also given below: