Lipids | Organic Chemistry 3

Lipids are studied in this chapter: classes of lipids, waxes, triglycerides, reactions of triglycerides and fatty acids, phospholipids, phosphoglycerides, steroid structure, cholesterol and other major steroids, biosynthesis of cholesterol, eicosanoids, prostaglandins, terpenes, classification and biosynthesis of terpenes.



Naturally occurring compounds that are extracted from cells using nonpolar solvents. Lipids are defined on the basis of a physical property rather than the presence of a particular functional group ⇒ lipids come in a wide variety of structures. All lipids have many C-C and C-H bonds, making them highly soluble in organic solvents and insoluble in water.

Complex lipids (or hydrolyzable lipids) are readily hydrolyzed in aqueous acid or base due to the presence of ester moieties, whereas simple lipids (or non-hydrolyzable lipids) are not hydrolyzed.


Classes of lipids:

Major classes of complex lipids are:

  • Waxes
  • Triglycerides
  • Phospholipids

Major classses of simples lipids are:

  • Steroids
  • Eicosanoids
  • Terpenes



Waxes are the simplest hydrolyzable lipids. They are high molecular weight esters formed from a fatty acid and an alcohol. Due to their long hydrocarbon chains, waxes are very hydrophobic and have high melting points.


Spermaceti wax:

Triglycerides and Fatty Acids Properties


Triglycerides are triesters formed from glycerol and 3 long-chain carboxylic acids (fatty acids). Triglycerides are used by mammals and plants for long-term energy storage.

Simple triglycerides are composed of 3 identical fatty acids, while mixed triglycerides have 2 or 3 different fatty acids.

Triglycerides that are solids at room temperature are called fats, while those that are liquids are called oils.


Properties of fatty acids:

  • Structure: Unbranched carboxylic acids, typically containing an even number of carbons (between 12 and 20).
  • Saturation: Some fatty acids are saturated (contain no C=C bonds), while others are unsaturated.
  • Melting points: The melting point of saturated fatty acids increases with increasing molecular weight. The presence of a cis double bond in an unsaturated fatty acid causes the melting point to decrease. Additional double bonds further lower the melting point.


Reactions of Triglycerides

Hydrolysis of triglycerides:

Conversion of a triglyceride into glycerol and 3 fatty acids. This process is called triglyceride saponification.


  1. Nucleophilic attack of the hydroxide on the carbonyl group of the fatty acids to form a tetrahedral intermediate.
  2. Loss of the leaving group, an alkoxide ion, to re-form the carbonyl.
  3. Deprotonation of the carboxylic acid with the alkoxide ion to form a carboxylate ion (shifting the equilibrium in favor of product formation).
  4. After the reaction is complete, protonation of the carboxylate ion in the presence of an acid.


Hydrogenation of unsaturated fatty acids:

Conversion of an unsaturated fatty acid into a saturated fatty acid using H2 and a transition metal catalyst (nickel or Pd-C).


Oxidation of unsaturated fatty acids:

Conversion of an unsaturated acid into a hydroperoxide in the presence of oxygen.


Transesterification of triglycerides:

Conversion of a triglyceride into glycerol and 3 fatty acid esters.


  1. Protonation of the carbonyl group to make it even more electrophilic.
  2. Nucleophilic attack of an alcohol on the carbonyl.
  3. Deprotonation to form a neutral tetrahedral intermediate.
  4. Protonation of the alkoxy group to make it a better leaving group.
  5. Loss of the leaving group, an alcohol, to re-form the carbonyl group.
  6. Deprotonation to form a fatty acid ester.

This transformation can also be achieved with base catalysis.


Structure of phospholipids:

Phospholipids are ester-like derivatives of phosphoric acid. The most abundant phospholipids are phosphoglycerides.



A phosphoglyceride is a phospholipid consisting of a glycerol backbone, 2 fatty acid chains, and a phosphoester group.The simplest type of phosphoglyceride is a phosphoric monoester called phosphatidic acid. At physiological pH, the ionized form predominates.


The most common phosphoglycerides are phosphoric acid diesters such as cephalins (R = ethanolamine) and lecithins (R = choline):


Lipid bilayers:

Phosphoglycerides are fundamental components of cell membranes, forming a lipid bilayer due to their amphipathic nature. This arrangement, with hydrophobic tails inward and hydrophilic heads outward, provides structural integrity and regulates the passage of molecules into and out of cells.


Steroid structure:

Steroids are a class of tetracyclic lipids that play a variety of roles in living organisms, including serving as hormones in animals and plants, regulating metabolic processes, controlling inflammation, and influencing the immune system.

They are characterized by a specific arrangement of four cycloalkane rings (3 six-membered rings and 1 five-membered ring). These rings are labeled using the letters A, B, C, and D. The carbon atoms in this system are numbered as shown.




Cholesterol is a steroid with 2 methyl groups attached at C10 and C13, and a side chain attached at C17. It is essential for the formation of cell membranes, the production of hormones, and synthesis of vitamin D. Cholesterol is the starting material for the synthesis of all other steroids.


Biosynthesis of cholesterol:

Conversion of squalene into cholesterol.


  1. Asymmetric epoxidation of squalene via enzymatic catalysis to form squalene oxide.

  2. Series of intramolecular cyclization reactions of the squalene oxide to form a protosterol cation.

  3. Series of carbocation rearrangements, including both methyl shifts and hydride shifts, to form a new 3o carbocation.

  4. Deprotonation of the carbocation to form an alkene called lanosterol,  the precursor of cholesterol.

  5. Multi-step process to convert lanosterol into cholesterol.


Other important steroids:

  • Sex hormones:

Steroids that regulate tissue growth and reproductive processes. There are 2 types of female sex hormones called estrogens and progestins. The male sex hormones are called androgens.

Femal sex hormones:

Male sex hormones:


  • Adrenocortical hormones:

Steroids secreted by the cortex of the adrenal gland. They are typically characterized by a carbonyl group or hydroxyl group at C11. Examples include cortisone and cortisol, which serve as anti-inflammatory agents and regulators of carbohydrate metabolism.



Eicosanoids are a group of biologically active compounds containing 20 carbon atoms derived from arachidonic acid. There are 4 types of eicosanoids: the prostaglandins, the leukotrienes, the thromboxanes, and the prostacyclins.

Each eicosanoid is associated with specific types of biological activity. In some cases, the effects are opposite. For example, thromboxanes induce blood platelet aggregation, whereas prostacyclins inhibit platelet aggregation.



Prostaglandins contain 20 carbon atoms and are characterized by a five-membered ring with 2 side chains.


Prostaglandins are biochemical regulators that are even more powerful than steroids. Unlike hormones, they are local mediators performing their function where they are synthesized and exhibit a wide array of biological activity (regulation of blood pressure, inflammation, kidney function ...)


Biosynthesis of prostaglandins:

Biosynthesis from arachidonic acid with the help of enzymes called cyclooxygenases.


  1. Abstraction of one of the hydrogens of arachidonic acid in the presence of cyclooxygenase to form a resonance-stabilized radical.

  2. Coupling between the resonance-stabilized radical and a molecule of oxygen O2.

  3. Coupling of a second molecule of oxygen followed by a rearrangement to form a bicyclic peroxy radical.

  4. Conversion of the peroxy radical into a hydroxyl group in the presence of cyclooxygenase.



Terpenes are naturally occuring lipids that are formed by linking multiple isoprene units together in various arrangements ⇒ the number of carbon atoms present in terpenes is a multiple of 5. During the biosynthesis of terpenes, isoprene units are generally connected head to tail.

Terpenes are characterized by their strong odor and are often responsible for the distinct scents and flavors associated with different plant species.


Classification of terpenes

Terpenes are classified based on units of 10 carbon atoms (2 isoprene units):

  • 10 carbon atoms = monoterpene
  • 15 carbon atoms = sesquiterpene
  • 20 carbon atoms = diterpene
  • 30 carbon atoms = triterpene


Biosynthesis of terpenes:

Althrough terpenes are formed by isoprene units, their building blocks are dimethylallyl pyrophosphate and isopentenyl pyrophosphate. The pyrophosphate, a diphosphate abbreviated as OPP, is a biological leaving group because it is a weak, resonance-stabilized base..


  • Biosynthesis of geranyl pyrophosphate:

Reaction between dimethylallyl pyrophosphate and isopentenyl pyrophosphate to form geranyl phosphate, the starting material for all other monoterpenes.


  1. Loss of the pyrophosphate leaving group to form a resonance-stabilized allylic carbocation.
  2. Nucleophilic attack of the π bond of isopentyl pyrophosphate to the allylic carbocation to form a new carbocation.
  3. Deprotonation to form geranyl pyrophosphate.


  • Biosynthesis of farnesyl pyrophosphate:

Reaction between geranyl pyrophosphate and isopentenyl pyrophosphate to form farnesyl phosphate, the starting material for all other sesquiterpenes and diterpenes.


  1. Loss of the pyrophosphate leaving group to form a resonance-stabilized allylic carbocation.
  2. Nucleophilic attack of the π bond of isopentyl pyrophosphate to the allylic carbocation to form a new carbocation.
  3. Deprotonation to form farnesyl pyrophosphate.

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Lipids are a diverse group of hydrophobic molecules that include several main classes: waxes, triglycerides, phospholipids, steroids, eicosanoids, and terpenes.

  • Waxes, long-chain fatty acids esterified to long-chain alcohols, serve as a protective coating for plants and animals, providing waterproofing and preventing desiccation.
  • Triglycerides, comprised of three fatty acids and a glycerol molecule, are the main form of stored energy in animals.
  • Phospholipids, which consist of two fatty acids, a phosphate group, and glycerol, play a crucial role in forming cell membranes due to their amphipathic nature.
  • Steroids, characterized by their four-ring structure, are important for many physiological processes, including hormone signaling with cholesterol being a key component in cellular membranes.
  • Eicosanoids, derived from fatty acids, function in inflammation and communication within the body
  • Terpenes, built from isoprene units, are involved in creating pigments and vitamins.

Saturated and unsaturated fatty acids differ primarily in the type of bonds between carbon atoms in their hydrocarbon chains: 

  • Saturated fatty acids have single bonds (C-C) between all carbon atoms, resulting in a straight chain. This allows them to pack closely together, leading to a higher melting point and a solid state at room temperature, commonly found in animal fats.
  • On the other hand, unsaturated fatty acids contain one or more double bonds (C=C) in their hydrocarbon chain, which introduces kinks that prevent tight packing. This results in a lower melting point, making them liquid at room temperature, as seen in plant oils.

The length and saturation of fatty acid chains play a significant role in determining the physical properties of lipids such as melting point and state:

  • Longer chains lead to higher van der Waals forces between molecules, resulting in higher melting points and more solid-like behavior at room temperature.
  • Conversely, shorter chains have lower van der Waals forces and therefore lower melting points, often being liquid at room temperature.

Saturation refers to the presence of double bonds in the fatty acid chains and also affects the physical properties of lipids:

  • Saturated fatty acids, without any double bonds, can pack tightly together, increasing intermolecular interactions and raising the melting point.
  • Unsaturated fatty acids have one or more cis double bonds that create kinks, preventing tight packing and reducing intermolecular forces, which lowers the melting point and makes the lipids more fluid.

Waxes play a crucial role in nature as protective coatings for plants and animals, aiding in water retention and defense against parasites and environmental factors. Structurally, waxes differ from fats and oils primarily in their composition; waxes are esters of long-chain alcohols with long-chain fatty acids, whereas fats and oils are triglycerides, composed of glycerol esters with three fatty acids. This structural difference makes waxes much more solid and less prone to rancidity compared to fats and oils.

Triglycerides undergo several reactions, including hydrolysis (or saponification), hydrogenation, oxidation, and transesterification.

  • Hydrolysis involves the reaction of triglycerides with a strong base, such as sodium hydroxide, to form fatty acids and glycerol.
  • Hydrogenation reduces unsaturated triglycerides to saturated forms, typically using hydrogen gas and a metal catalyst.
  • Oxidation leads to hydroperoxide.
  • Transesterification involves the reaction of triglycerides with excess alcohol, yielding fatty acid esters and glycerol, an important process in biodiesel production.

The hydrolysis of triglycerides is vitally important in biochemistry because it breaks down fats into glycerol and fatty acids, which can then be used as sources of energy for the body. This process, known as lipolysis, provides the necessary substrates for beta-oxidation, where fatty acids are further broken down in the mitochondria to yield large quantities of ATP, the cell's energy currency. Moreover, the glycerol backbone can enter glycolysis or gluconeogenesis pathways, providing additional flexibility in energy metabolism. The release of fatty acids also allows for the construction of cell membranes and the synthesis of signaling molecules, which are essential for numerous biological functions.

Phospholipids are a class of lipids containing a phosphate group, a glycerol molecule, two fatty acid chains, and a polar head group. They are essential components of cell membranes, where they form a lipid bilayer structure.

  • Structurally, phospholipids contain a phosphate group, a glycerol molecule, two fatty acid chains, and a polar head group, whereas triglycerides consist of three fatty acid chains esterified to a glycerol backbone.
  • Functionally, phospholipids are critical structural components of cell membranes, contributing to their fluidity, flexibility, and selective permeability. Triglycerides, on the other hand, serve primarily as energy storage molecules, providing a concentrated source of metabolic energy when broken down by hydrolysis.

Phospholipids have a hydrophilic (water-attracting) "head" and two hydrophobic (water-repellent) "tails." This amphipathic nature allows them to form bilayers that make up cell membranes. In aqueous environments, the hydrophilic heads face the water on both sides of the membrane, while the hydrophobic tails face towards each other, creating a semi-permeable barrier that regulates what enters and exits the cell.

Steroids are a class of lipids characterized by a carbon skeleton composed of four fused rings, typically three six-membered rings and one five-membered ring. This structure is commonly known as the steroid nucleus.

The major types of sex hormones include estrogen, progesterone, and testosterone.

  • Estrogens are primarily female sex hormones responsible for the development of female reproductive organs and secondary sexual characteristics.
  • Progesterone plays a critical role in regulating the menstrual cycle and supporting pregnancy.
  • Testosterone is the primary male sex hormone involved in the development of male reproductive organs and secondary sexual characteristics.

Eicosanoids are a family of bioactive lipid compounds derived from twenty-carbon fatty acids, typically arachidonic acid. They include prostaglandins, thromboxanes, leukotrienes, and other related compounds.

Eicosanoids act as local hormones and perform a wide variety of physiological roles, including the modulation of inflammation, immune responses, blood clotting, and maintenance of blood pressure. Due to their role in inflammation and pain, drugs that target the synthesis or activity of eicosanoids, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are widely used as therapeutic agents.

Prostaglandins contain 20 carbon atoms and are characterized by a five-membered ring with 2 side chains. They are synthesized from arachidonic acid, a polyunsaturated fatty acid found in cell membranes. The enzymatic conversion of arachidonic acid by cyclooxygenase enzymes leads to the formation of prostaglandin H2, a bicyclic compound which serves as a precursor for other prostaglandins.


Terpenes are naturally occuring lipids characterized by multiple isoprene units, which can be arranged in linear, branched, or cyclic structures. Terpenes are classified based on the number of isoprene (5 carbon) units they contain. For example, monoterpenes consist of two isoprene units, sesquiterpenes have three, diterpenes have four, and so on.

Terpenes are biosynthesized by the condensation of the five-carbon precursors isopentenyl diphosphate and dimethylallyl diphosphate. These precursors undergo various enzymatic reactions catalyzed by terpene synthase enzymes. These enzymes facilitate cyclization, rearrangement, and addition reactions leading to the formation of various terpene structures.