Carey - Organic Chemistry - chapt26

Carey - Organic Chemistry - chapt26

(Parte 1 de 5)


Lipids differ from the other classes of naturally occurring biomolecules (carbohydrates, proteins, and nucleic acids) in that they are more soluble in non-to-weakly polar solvents (diethyl ether, hexane, dichloromethane) than they are in water. They include a variety of structural types, a collection of which is introduced in this chapter.

In spite of the number of different structural types, lipids share a common biosynthetic origin in that they are ultimately derived from glucose. During one stage of carbohydrate metabolism, called glycolysis,glucose is converted to lactic acid. Pyruvic acid is an intermediate.

In most biochemical reactions the pH of the medium is close to 7. At this pH, carboxylic acids are nearly completely converted to their conjugate bases. Thus, it is common practice in biological chemistry to specify the derived carboxylate anion rather than the carboxylic acid itself. For example, we say that glycolysis leads to lactateby way of pyruvate.

Pyruvate is used by living systems in a number of different ways. One pathway, the one leading to lactate and beyond, is concerned with energy storage and production. This is not the only pathway available to pyruvate, however. Asignificant fraction of it is converted to acetate for use as a starting material in the biosynthesis of more complex substances, especially lipids. By far the major source of lipids is biosynthesisvia acetate and this chapter is organized around that theme. We’l begin by looking at the reaction in which acetate (two carbons) is formed from pyruvate (three carbons).

CH3CCO2H Pyruvic acid

CH3CHCO2H Lactic acid

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The form in which acetate is used in most of its important biochemical reactions is acetyl coenzyme A(Figure 26.1a). Acetyl coenzyme Ais a thioester(Section 20.12). Its formation from pyruvate involves several steps and is summarized in the overall equation:

All the individual steps are catalyzed by enzymes. NAD (Section 15.1) is required as an oxidizing agent, and coenzyme A(Figure 26.1b) is the acetyl group acceptor. Coenzyme Ais a thiol;its chain terminates in a sulfhydryl(±SH) group. Acetylation of the sulfhydryl group of coenzyme Agives acetyl coenzyme A.

As we saw in Chapter 20, thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution. They also contain a greater proportion of enol at equilibrium. Both properties are apparent in the properties of acetyl coenzyme A. In some reactions it is the carbonyl group of acetyl coenzyme Athat reacts; in others it is the - carbon atom.

CH3CSCoAAcetyl coenzyme A


Enol form reaction at carbonnucleophilic acyl substitution


Pyruvic acid


Acetyl coenzyme A CoASHCoenzyme A

Oxidized form of nicotinamide adenine dinucleotide

Reduced form of nicotinamide adenine dinucleotide


Carbon dioxide H Proton




Coenzyme A (abbreviation: CoASH) R H

Coenzyme A was isolated and identified by Fritz Lipmann, an American biochemist. Lipmann shared the 1953 Nobel Prize in physiology or medicine for this work.

FIGURE 26.1 Structures of (a) acetyl coenzyme A and (b) coenzyme A.

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We’l see numerous examples of both reaction types in the folowing sections.

Keep in mind that in vivo reactions (reactions in living systems) are enzyme-catalyzed and occur at rates that are far greater than when the same transformations are carried out in vitro (“in glass”) in the absence of enzymes. In spite of the rapidity with which enzyme-catalyzed reactions take place, the nature of these transformations is essentially the same as the fundamental processes of organic chemistry described throughout this text.

Fatsare one type of lipid. They have a number of functions in living systems, including that of energy storage. Although carbohydrates serve as a source of readily available energy, an equal weight of fat delivers over twice the amount of energy. It is more efficient for an organism to store energy in the form of fat because it requires less mass than storing the same amount of energy in carbohydrates or proteins.

How living systems convert acetate to fats is an exceedingly complex story, one that is well understood in broad outline and becoming increasingly clear in detail as well. We will examine several aspects of this topic in the next few sections, focusing mostly on its structural and chemical features.


Fats and oils are naturally occurring mixtures of triacylglycerols,also called triglycerides.They differ in that fats are solids at room temperature and oils are liquids. We generally ignore this distinction and refer to both groups as fats. Triacylglycerols are built on a glycerol framework.

All three acyl groups in a triacylglycerol may be the same, all three may be different, or one may be different from the other two.

Figure 26.2 shows the structures of two typical triacylglycerols, 2-oleyl-1,3- distearylglycerol (Figure 26.2a) and tristearin (Figure 26.2b). Both occur naturally—in cocoa butter, for example. All three acyl groups in tristearin are stearyl (octadecanoyl) groups. In 2-oleyl-1,3-distearylglycerol, two of the acyl groups are stearyl, but the one in the middle is oleyl (cis-9-octadecenoyl). As the figure shows, tristearin can be prepared by catalytic hydrogenation of the carbon–carbon double bond of 2-oleyl-1,3- distearylglycerol. Hydrogenation raises the melting point from 43°C in 2-oleyl-1,3- distearylglycerol to 72°C in tristearin and is a standard technique in the food industry for converting liquid vegetable oils to solid “shortenings.” The space-filling models of the two show the flatter structure of tristearin, which allows it to pack better in a crystal lattice than the more irregular shape of 2-oleyl-1,3-distearylglycerol permits. This irregular shape is a direct result of the cis double bond in the side chain.

Hydrolysis of fats yields glycerol and long-chain fatty acids.Thus, tristearin gives glycerol and three molecules of stearic acid on hydrolysis. Table 26.1 lists a few representative fatty acids. As these examples indicate, most naturally occurring fatty acids possess an even number of carbon atoms and an unbranched carbon chain. The carbon



A triacylglycerol

An experiment describing the analysis of the triglyceride composition of several vegetable oils is described in the May 1988 issue of the Journal of Chemical Education(p. 464–466).

Strictly speaking, the term “fatty acid” is restricted to those carboxylic acids that occur naturally in triacylglycerols. Many chemists and biochemists, however, refer to all unbranched carboxylic acids, irrespective of their origin and chain length, as fatty acids.

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2-Oleyl-1,3-distearylglycerol (mp 43°C)Tristearin (mp 72°C)

FIGURE 26.2 The structures of two typical triacylglycerols. (a) 2-Oleyl-1,3-distearylglycerol is a naturally occurring triacylglycerol found in cocoa butter. The cis double bond of its oleyl group gives the molecule a shape that interferes with efficient crystal packing. (b) Catalytic hydrogenation converts 2-oleyl-1,3-distearylglycerol to tristearin. Tristearin has a higher melting point than 2-oleyl-1,3-distearylglycerol.

TABLE 26.1Some Representative Fatty Acids Systematic name

Dodecanoic acid Tetradecanoic acid Hexadecanoic acid Octadecanoic acid Icosanoic acid

Common name

Lauric acid Myristic acid Palmitic acid Stearic acid Arachidic acid

Oleic acid Linoleic acid

Linolenic acid Arachidonic acid

Structural formula

Saturated fatty acids

Unsaturated fatty acids

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PROBLEM 26.1What fatty acids are produced on hydrolysis of 2-oleyl-1,3- distearylglycerol? What other triacylglycerol gives the same fatty acids and in the same proportions as 2-oleyl-1,3-distearylglycerol?

Afew fatty acids with trans double bonds (trans fatty acids) occur naturally, but the major source of trans fats comes from the processing of natural fats and oils. In the course of hydrogenating some of the double bonds in a triacylglycerol, stereoisomerization can occur, converting cis double bonds to trans. Furthermore, the same catalysts that promote hydrogenation promote the reverse process—dehydrogenation—by which new double bonds, usually trans, are introduced in the acyl group.

Fatty acids occur naturaly in forms other than as glyceryl triesters, and we’l see numerous examples as we go through the chapter. One recently discovered fatty acid derivative is anandamide.

Anandamide is an ethanolamine (H2NCH2CH2OH) amide of arachidonic acid (see Table 26.1). It was isolated from pig’s brain in 1992 and identified as the substance that nor- mally binds to the “cannabinoid receptor.” The active component of marijuana, 9-tetrahydrocannabinol (THC), must exert its effect by binding to a receptor, and scientists had long wondered what compound in the body was the natural substrate for this binding site. Anandamide is that compound, and it is now probably more appropriate to speak of cannabinoids binding to the anandamide receptor instead of vice versa. Anandamide seems to be involved in moderating pain. Once the identity of the “endogenous cannabinoid” was known, scientists looked specifically for it and found it in some surprising places—chocolate, for example.

Fatty acids are biosynthesized by way of acetyl coenzyme A. The following section outlines the mechanism of fatty acid biosynthesis.


We can describe the major elements of fatty acid biosynthesis by considering the formation of butanoic acid from two molecules of acetyl coenzyme A. The “machinery” responsible for accomplishing this conversion is a complex of enzymes known as fatty acid synthetase.Certain portions of this complex, referred to as acyl carrierprotein (ACP),bear a side chain that is structurally similar to coenzyme A. An important early step in fatty acid biosynthesis is the transfer of the acetyl group from a molecule of acetyl coenzyme Ato the sulfhydryl group of acyl carrier protein.


Acetyl coenzyme A


S-Acetyl acyl carrier protein HSCoACoenzyme A

Acyl carrier protein


Instead of being a triacyl ester of glycerol, the fat substitute olestra is a mixture of hexa-, hepta-, and octaacyl esters of sucrose in which the acyl groups are derived from fatty acids. Olestra has many of the physical and taste properties of a fat but is not metabolized by the body and contributes no calories. For more about olestra, see the April 1997 issue of the Journal of Chemical Education,p. 370–372.

The September 1997 issue of the Journal of Chemical Education (p. 1030–1032) contains an article entitled “Trans Fatty Acids.”

Other than that both are lipids, there are no obvious structural similarities between anandamide and THC.

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PROBLEM 26.2Using HSCoA and HS±ACP as abbreviations for coenzyme A and acyl carrier protein, respectively, write a structural formula for the tetrahedral intermediate in the preceding reaction.

Asecond molecule of acetyl coenzyme Areacts with carbon dioxide (actually bicarbonate ion at biological pH) to give malonyl coenzyme A:

Formation of malonyl coenzyme Ais followed by a nucleophilic acyl substitution, which transfers the malonyl group to the acyl carrier protein as a thioester.

When both building block units are in place on the acyl carrier protein, carbon–carbon bond formation occurs between the -carbon atom of the malonyl group and the carbonyl carbon of the acetyl group. This is shown in step 1 of Figure 26.3. Carbon–carbon bond formation is accompanied by decarboxylation and produces a four-carbon acetoacetyl (3-oxobutanoyl) group bound to acyl carrier protein.

The acetoacetyl group is then transformed to a butanoyl group by the reaction sequence illustrated in steps 2 to 4 of Figure 26.3.

The four carbon atoms of the butanoyl group originate in two molecules of acetyl coenzyme A. Carbon dioxide assists the reaction but is not incorporated into the product. The same carbon dioxide that is used to convert one molecule of acetyl coenzyme Ato malonyl coenzyme Ais regenerated in the decarboxylation step that accompanies carbon–carbon bond formation.

Successive repetitions of the steps shown in Figure 26.3 give unbranched acyl groups having 6, 8, 10, 12, 14, and 16 carbon atoms. In each case, chain extension occurs by reaction with a malonyl group bound to the acyl carrier protein. Thus, the biosynthesis of the 16-carbon acyl group of hexadecanoic (palmitic) acid can be represented by the overall equation:


Acyl carrier protein 21 H2OWater

Oxidized form of coenzyme


Carbon dioxide

S-Hexadecanoyl acyl carrier protein


Reduced form of coenzyme

Hydronium ion

S-Acetyl acyl carrier protein


S-Malonyl acyl carrier protein


Acyl carrier protein


Malonyl coenzyme A

HSCoACoenzyme A S-Malonyl acyl carrier protein



Acetyl coenzyme A


Malonyl coenzyme A H2OWater

HCO3 Bicarbonate

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PROBLEM 26.3By analogy to the intermediates given in steps 1–4 of Figure 26.3, write the sequence of acyl groups that are attached to the acyl carrier protein in the conversion of toCH3(CH2)12CS±ACP

dioxide. Presumably decarboxylation gives an enol, which attacks the acetyl group.

Step 1: An acetyl group is transferred to the carbon atom of the malonyl group with evolution of carbon

NADPH as a coenzyme. (NADPH is the phosphate ester of NADH and reacts similarly to it.)

Step 2: The ketone carbonyl of the acetoacetyl group is reduced to an alcohol function. This reduction requires



Acetyl and malonyl groups bound to acyl carrier protein


S-Acetoacetyl acyl carrier protein

Acyl carrier protein (anionic form)


S-Acetoacetyl acyl carrier protein

Reduced form of coenzyme

Hydronium ion

S-3-Hydroxybutanoyl acyl carrier protein

Oxidized form of coenzyme

Water OH

Step 3: Dehydration of the -hydroxy acyl group.


S-3-Hydroxybutanoyl acyl carrier protein

S-2-Butenoyl acyl carrier protein

H2O Water

Step 4: Reduction of the double bond of the , -unsaturated acyl group. This step requires NADPH as a coenzyme.

S-2-Butenoyl acyl carrier protein

Reduced form of coenzyme

Hydronium ion

S-Butanoyl acyl carrier protein

Oxidized form of coenzyme

FIGURE 26.3 Mechanism of biosynthesis of a butanoyl group from acetyl and malonyl building blocks.

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This phase of fatty acid biosynthesis concludes with the transfer of the acyl group from acyl carrier protein to coenzyme A. The resulting acyl coenzyme Amolecules can then undergo a number of subsequent biological transformations. One such transformation is chain extension, leading to acyl groups with more than 16 carbons. Another is the introduction of one or more carbon–carbon double bonds. Athird is acyl transfer from sulfur to oxygen to form esters such as triacylglycerols. The process by which acyl coenzyme Amolecules are converted to triacylglycerols involves a type of intermediate called a phospholipidand is discussed in the following section.

(Parte 1 de 5)