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Organic Chemistry
Table of Contents
Unit 8 Overview: Alkenes
8.1 Preparing Alkenes: A Preview of Elimination Reactions
8.2 Halogenation of Alkenes: Addition of X2
8.3 Halohydrins from Alkenes: Addition of HO-X
8.4 Hydration of Alkenes: Addition of H2O by Oxymercuration
8.5 Hydration of Alkenes: Addition of H2O by Hydroboration
8.6 Reduction of Alkenes: Hydrogenation
8.7 Oxidation of Alkenes: Epoxidation and Hydroxylation
8.8 Oxidation of Alkenes: Cleavage to Carbonyl Compounds
8.9 Addition of Carbenes to Alkenes: Cyclopropane Synthesis
8.10 Radical Additions to Alkenes: Chain-Growth Polymers
8.11 Biological Additions of Radicals to Alkenes
8.12 Reaction Stereochemistry: Addition of H2O to an Achiral Alkene
8.13 Reaction Stereochemistry: Addition of H2O to a Chiral Alkene

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8.11 Biological Additions of Radicals to Alkenes

Citation:

Radical additions to alkenes are crucial in biological processes like prostaglandin biosynthesis. Enzymes like prostaglandin H synthase control these reactions, ensuring precise additions at specific locations on molecules like arachidonic acid.

Unlike lab-based radical reactions, biological systems exhibit high specificity due to enzyme involvement. This control allows for the formation of complex molecules like prostaglandins without unwanted side reactions, showcasing nature's remarkable precision in chemical processes.

Biological Radical Additions to Alkenes

Prostaglandin biosynthesis mechanism

  • Arachidonic acid, a 20-carbon polyunsaturated fatty acid (PUFA), serves as the precursor for prostaglandin synthesis
  • Prostaglandin H synthase (PGHS) catalyzes the conversion of arachidonic acid to prostaglandin H2 (PGH2) through a series of radical additions
    • PGHS contains two distinct active sites: a cyclooxygenase (COX) and a peroxidase (POX) that work in tandem to facilitate the reaction
  • The cyclooxygenase reaction involves a sequence of radical additions:
    1. Tyrosine385 residue in the COX active site undergoes oxidation by the POX site, generating a highly reactive tyrosyl radical
    2. The tyrosyl radical abstracts a hydrogen atom from C13 of arachidonic acid, creating a delocalized pentadienyl radical intermediate (an example of hydrogen abstraction)
    3. The pentadienyl radical reacts with two molecules of O2 at C11 and C15, forming a bicyclic peroxyl radical species
    4. The peroxyl radical undergoes cyclization, generating a cyclopentane ring and a new carbon-centered radical
    5. The carbon-centered radical is trapped by a second O2 molecule, resulting in the formation of PGG2, an unstable endoperoxide
  • PGG2 is then reduced by the POX site to form PGH2, which serves as the precursor for the synthesis of various prostaglandins (PGE2, PGF2α) and thromboxanes (TXA2)

Biological vs laboratory radical reactions

  • Biological radical reactions, such as prostaglandin biosynthesis, exhibit a high degree of control and specificity due to the involvement of enzymes
    • Enzymes ensure that radical additions occur in a precise sequence and at specific locations on the substrate molecule
    • The radicals generated in biological systems are short-lived and quickly quenched, minimizing the occurrence of unwanted side reactions
  • In contrast, laboratory-based radical addition reactions often lack the same level of control and specificity
    • Radicals generated in the lab tend to be longer-lived and can engage in various side reactions, leading to the formation of undesired products
    • Radical additions in the lab often result in a mixture of products, including regioisomers (different positions of addition) and stereoisomers (different spatial arrangements)
    • Controlling the selectivity and specificity of radical additions in the lab poses a significant challenge due to the high reactivity and instability of radical intermediates

Enzyme-facilitated radical reactions

  • Enzymes, such as prostaglandin H synthase (PGHS), provide a carefully controlled environment for radical reactions to occur with high precision
    • The active sites of enzymes are designed to bind substrates in a specific orientation, ensuring regioselectivity (specific position) and stereoselectivity (specific spatial arrangement)
    • Enzymes can shield radical intermediates from the surrounding environment, preventing unwanted side reactions and off-target effects
  • In prostaglandin biosynthesis, PGHS facilitates precise radical additions through several mechanisms:
    • The cyclooxygenase (COX) active site positions arachidonic acid in a specific orientation, allowing for selective hydrogen abstraction from C13
    • The enzyme's active site residues stabilize the pentadienyl radical intermediate, promoting the desired addition of O2 at C11 and C15
    • The enzyme's structure facilitates the cyclization of the peroxyl radical, ensuring the formation of the cyclopentane ring
    • The peroxidase (POX) active site efficiently reduces PGG2 to PGH2, preventing the accumulation of reactive intermediates that could lead to side reactions
  • The close proximity of the COX and POX active sites in PGHS allows for the rapid transfer of intermediates, minimizing the likelihood of side reactions and ensuring the efficient production of prostaglandins

Free Radical Reactions in Biological Systems

  • Free radicals play crucial roles in various biological processes, including prostaglandin biosynthesis
  • Enzyme catalysis is essential for controlling free radical reactions in living organisms
  • Oxidation of certain enzyme residues can generate reactive radical species that initiate cascades of controlled reactions
  • Cyclization reactions involving free radicals are common in the biosynthesis of complex biological molecules, such as prostaglandins

Key Terms to Review (29)

Stereoisomers: Stereoisomers are molecules that have the same molecular formula and connectivity, but differ in the three-dimensional arrangement of their atoms in space. This spatial arrangement of atoms leads to different physical and chemical properties, even though the atoms are connected in the same way.
Regioselectivity: Regioselectivity refers to the preference of a chemical reaction to occur at a specific site or region of a molecule, leading to the formation of one regioisomeric product over another. This concept is particularly important in the context of electrophilic addition reactions of alkenes, electrophilic aromatic substitution, and other organic transformations.
Hydrogen Abstraction: Hydrogen abstraction is a fundamental reaction in organic chemistry where a hydrogen atom is removed from a molecule, often by a reactive species such as a radical or a base. This process is central to various topics in organic chemistry, including radical reactions, biological additions of radicals to alkenes, and the preparation of alkyl halides from alkanes and alkenes.
Radical Addition: Radical addition is a type of organic reaction where a radical species, typically a hydrogen radical or a halogen radical, adds to an alkene or alkyne to form a new carbon-centered radical. This process is an important concept in understanding both radical reactions and the biological additions of radicals to alkenes.
Stereoselectivity: Stereoselectivity refers to the preference of a chemical reaction to form one stereoisomeric product over another. It is a crucial concept in organic chemistry that describes the ability of a reaction to control the spatial arrangement of atoms in the final product.
Arachidonic Acid: Arachidonic acid is a polyunsaturated fatty acid that plays a crucial role in various biological processes, particularly in the context of prostaglandin synthesis and the body's inflammatory response. It is a key precursor for the production of eicosanoids, a group of signaling molecules that regulate a wide range of physiological functions.
Oxidation: Oxidation is a fundamental chemical process in which a substance loses electrons, resulting in an increase in its oxidation state. This term is central to understanding various reactions and transformations in organic chemistry, from the hydration of alkenes to the oxidation of alcohols and aldehydes.
Free Radical: A free radical is a highly reactive chemical species that contains an unpaired electron in its outer shell. These unstable molecules are constantly seeking to pair up their unpaired electron, making them highly reactive and capable of initiating chain reactions in various chemical processes, including those involved in the formation of chain-growth polymers and biological additions to alkenes.
Prostaglandin: Prostaglandins are a group of lipid compounds derived from arachidonic acid that act as signaling molecules in the body, mediating various physiological and pathological processes. They are particularly relevant in the context of biological additions of radicals to alkenes.
Pentadienyl Radical: The pentadienyl radical is a resonance-stabilized organic radical species containing a conjugated system of five carbon atoms with one unpaired electron. It is an important intermediate in various biological processes involving the addition of radicals to alkenes.
Carbon-Centered Radical: A carbon-centered radical is a highly reactive species that contains an unpaired electron on a carbon atom. These radicals are intermediate species that play a crucial role in various chemical reactions, including those found in biological systems, such as the additions of radicals to alkenes discussed in Section 8.11.
PGHS: PGHS, or prostaglandin H synthase, is a key enzyme involved in the biosynthesis of prostaglandins and other eicosanoids. It plays a crucial role in the biological additions of radicals to alkenes, a process that is central to various physiological and pathological processes in the body.
Regioisomers: Regioisomers are a type of structural isomers that differ in the position of a functional group or substituent within the molecule. These positional isomers have the same molecular formula but the atoms are arranged differently, leading to distinct chemical and physical properties.
PGG2: PGG2, or Prostaglandin G2, is an important intermediate in the cyclooxygenase (COX) pathway of arachidonic acid metabolism. It serves as a precursor to various prostaglandins and thromboxanes, which are potent lipid signaling molecules involved in a wide range of physiological and pathological processes.
Thromboxane: Thromboxane is a potent vasoconstrictor and platelet aggregator produced by activated platelets and other cells. It plays a crucial role in the biological additions of radicals to alkenes within the context of 8.11 Biological Additions of Radicals to Alkenes.
Endoperoxide: An endoperoxide is a cyclic organic compound containing two oxygen atoms bonded to a pair of adjacent carbon atoms within a ring structure. This structural feature is particularly relevant in the context of biological additions of radicals to alkenes, as endoperoxides can form as intermediates in these reactions.
COX: COX, or cyclooxygenase, is an enzyme that plays a crucial role in the biological additions of radicals to alkenes. It is responsible for the conversion of arachidonic acid, a polyunsaturated fatty acid, into prostaglandins and other eicosanoids, which are important signaling molecules involved in various physiological and pathological processes.
Enzyme Catalysis: Enzyme catalysis is the process by which enzymes, which are biological catalysts, accelerate the rate of chemical reactions in living organisms. Enzymes achieve this by lowering the activation energy required for a reaction to occur, allowing it to proceed more rapidly under physiological conditions.
PUFA: PUFA, or polyunsaturated fatty acids, are a type of fatty acid that contain multiple double bonds in their carbon chain structure. These fatty acids are essential for various biological functions and are commonly found in plant-based oils, fish, and certain nuts and seeds.
Cyclooxygenase: Cyclooxygenase (COX) is an enzyme that catalyzes the first step in the biosynthesis of prostaglandins, prostacyclin, and thromboxanes - a group of lipid-based signaling molecules known as eicosanoids. This enzyme plays a crucial role in the body's inflammatory response and pain perception.
Peroxidase: Peroxidase is an enzyme that catalyzes the reduction of hydrogen peroxide (H2O2) to water (H2O) and an oxidized substrate. It plays a crucial role in various biological processes, including the oxidation of organic compounds and the regulation of cellular redox balance.
Prostaglandin H Synthase: Prostaglandin H synthase, also known as cyclooxygenase (COX), is a key enzyme involved in the biosynthesis of prostaglandins, prostacyclins, and thromboxanes. It catalyzes the conversion of arachidonic acid into prostaglandin H2, which serves as a precursor for various eicosanoid signaling molecules that regulate important physiological processes.
Tyrosyl Radical: The tyrosyl radical is a reactive species that forms during the catalytic cycle of certain enzymes, such as ribonucleotide reductase, which is essential for DNA synthesis. This radical plays a crucial role in the biological addition of radicals to alkenes, a process known as 8.11 Biological Additions of Radicals to Alkenes.
POX: POX refers to a class of radical addition reactions that occur in biological systems, where a radical species adds to an alkene to form a new carbon-carbon bond. These reactions are particularly important in the context of lipid metabolism and the modification of unsaturated fatty acids.
PGH2: PGH2, or Prostaglandin H2, is a key intermediate in the biosynthesis of various prostaglandins and other eicosanoids, which are important signaling molecules involved in a wide range of physiological and pathological processes in the body.
Cyclization: Cyclization is the process of forming a cyclic structure from an acyclic precursor molecule. This term is particularly relevant in the context of various organic chemistry reactions and processes, where the formation of rings plays a crucial role in the synthesis of complex molecules and the understanding of biological systems.
Prostaglandin H2: Prostaglandin H2 (PGH2) is a key intermediate in the biosynthesis of various prostaglandins, thromboxanes, and prostacyclins, which are important lipid signaling molecules involved in a wide range of physiological and pathological processes in the body.
Polyunsaturated Fatty Acid: Polyunsaturated fatty acids (PUFAs) are a type of fat molecule that contain multiple double bonds in their carbon chain structure. These unsaturated fats are an important component of cell membranes and play a crucial role in various biological processes, including the context of 8.11 Biological Additions of Radicals to Alkenes.
Peroxyl Radical: A peroxyl radical is a highly reactive species formed during the oxidation of organic compounds, particularly in the context of lipid peroxidation. These radicals play a crucial role in the biological additions of radicals to alkenes, a key process in understanding the effects of oxidative stress on living systems.