Fundamentals of Bioorganic Chemistry (Study Guide) - H. O. Syrova - 2018

Topic

Reactivity of bioorganic compounds.

Saturated, unsaturated and aromatic hydrocarbons, alcohols and phenols, amines

Relevance of the topic. Transformations of Organic compounds form The basis of life processes. Their behavior in the living Organism is determined by their composition, Structure, and chemical properties. Therefore, knowledge of The chemical properties of key classes of organic compounds is essential for understanding, at THE MOLECULAR LEVEL, the chemical processes occurring in living organisms during METABOLISM. The chemical behavior of Biopolymers, their metabolites, BIOREGULATORS, and drugs is determined by the shape and Spatial Structure of their molecular carbon Skeleton, The Nature of their chemical bonds, and the presence of functional groups. Consequently, the issues covered in this topic are crucial for the successful study of biochemistry, physiology, pharmacology, and hygiene.

General objective: to develop The ability to predict the chemical behavior of BIOLOGICALLY ACTIVE SUBSTANCES in living organisms during metabolic processes based on the knowledge of the Chemical properties of Major Classes of organic compounds.

Specific objectives:

1. Be able to use knowledge of the electronic structure of chemical bonds and functional groups to explain the chemical properties of organic compounds.

2. Be able to characterize The behavior of organic compounds in the following reactions:

✵ free-radical substitution;

✵ electrophilic addition;

✵ electrophilic substitution;

✵ nucleophilic substitution;

✵ acid-base reactions.

3. Be able to explain The Influence of substituents on the reactivity of functional groups.

Theoretical questions

1. Homolytic and heterolytic Cleavage of covalent bonds. Free radicals. Electrophilic and nucleophilic Reagents.

2. Reactivity of Hydrocarbons and hydrocarbon radicals:

✵ free-radical substitution reactions. Lipid Peroxidation;

✵ electrophilic addition to unsaturated compounds, the influence of electronic effects of substituents, acid catalysis;

✵ electrophilic substitution in Aromatic Compounds. Directing effects of substituents in the benzene ring and heteroatoms in heterocycles.

3. Hydroxyl-containing compounds - alcohols and phenols:

✵ acidity;

✵ nucleophilic substitution;

✵ oxidation.

4. Amines:

✵ basicity;

✵ alkylation.

1. The reactivity of organic compounds is determined by their composition, the electronic origin of their chemical bonds, and the spatial arrangement of atoms in their molecules. Chemical interaction between molecules must be preceded by the cleavage of bonds in each of them. The cleavage of a covalent bond between two atoms can occur in the following ways:

In the first case, each atom departs with one electron, resulting in The formation of particles that possess unpaired electrons. These are called free radicals, and the cleavage is referred to as homolytic bond cleavage.

In other cases, one of the atoms may retain both electrons upon cleavage, resulting in the formation of ions. Such cleavage is called heterolytic bond cleavage. Free radicals and ions serve as reaction intermediates in many organic compounds.

The Mechanism of bond cleavage depends on its polarity: the more polar the bond, the easier the heterolytic cleavage occurs. Process conditions also exert a significant influence: free radical reactions proceed primarily in the gas phase and in nonpolar Solvents, whereas ionic reactions occur in polar solvents.

If, during heterolytic bond cleavage, the carbon atom acquires a negative charge, the species is called a carbanion; if it acquires a positive charge, it is called a carbocation.

Carbanions readily interact with electrophilic reagents—electron-deficient species possessing vacant orbitals. Typical Examples of electrophiles include H⁺, SO₃, and AlCl₃. Carbocations are capable of reacting with nucleophilic reagents—species possessing an electron pair capable of forming a bond. Sometimes these species carry a negative charge. Examples of nucleophilic reagents include OH^-, Br^--, NH₃, and amines.

Depending on the type of intermediate species formed, radical, electrophilic, and nucleophilic reactions are distinguished.

2. The bonds between sp³-hybridized carbon atoms and with hydrogen atoms are often of low polarity (unless adjacent to a substituent that differs significantly in electronegativity from the carbon atom) and quite strong. Therefore, their heterolytic cleavage requires specific conditions (catalysts). At the same time, these bonds readily undergo homolytic cleavage. In this case, radical substitution reactions occur, wherein hydrogen atoms are replaced by other atoms or groups of atoms.

Radical reactions consist of three stages: initiation, chain propagation, and chain termination.

Free radicals are active intermediates in certain enzymatic processes. The rate of radical reactions is normally regulated by the presence of antioxidants, an example of which is vitamin E (tocopherol). This rate increases during Pregnancy, the growth of malignant neoplasms, and particularly upon radioactive irradiation (radiation sickness).

An example of a radical reaction is lipid peroxidation, in which Unsaturated Fatty acids that make up Cell membranes are subjected to radical attack. Under radioactive irradiation, Water molecules can break down into radicals: Н: ОН > H• + •ОН.

Hydroxyl radicals attack the unsaturated acid molecule at the methylene group adjacent to the double bond, because this yields a radical stabilized by the participation of the unpaired electron in conjugation with the electrons of the π-bond.

Next, the organic radical interacts with a biradical oxygen molecule to form unstable hydroperoxides, which decompose to yield aldehydes that are subsequently oxidized to acids—the final products of the reaction. The consequence of peroxidation is the destruction of cell membranes.

The inhibitory effect of vitamin E is due to its ability to scavenge radicals formed within Cells:

In the resulting phenoxyl radical, the unpaired electron is conjugated with the π-electron cloud of the aromatic ring, which imparts relative stability to it.

For unsaturated hydrocarbons containing carbon atoms in the sp²- or sp-hybridized state, typical reactions proceed with the Cleavage of the π-bond, i.e., addition reactions. These reactions can occur via both radical and ionic mechanisms. In the latter case, electrophilic addition takes place.

For example:

As a result of the initial interaction between bromine and the electrons of the double bond, the bromine molecule becomes polarized, forming an unstable π-complex. This transitions into a carbocation, in which bromine is bonded to carbon via a σ-bond. The process concludes with an attack by the Br^- anion, leading to the Formation of the final reaction product. Electrophilic addition reactions are frequently catalyzed by acids. In such cases, the formation of carbocations occurs through protonation. This happens, for instance, during the Hydration of alkenes in the presence of sulfuric acid:

A water molecule adds to the resulting carbocation via the lone electron pairs of the oxygen atom. An unstable oxonium alkyl derivative is formed, which stabilizes with the release of a proton.

The consequence of having a shared π-electron cloud spanning the entire conjugated system is the ability of such systems to enter into reactions as a single block. For example, 1,3-butadiene undergoes 1,4-addition, meaning the addition occurs at the terminal atoms of the conjugated system:

The reaction proceeds via an electrophilic addition mechanism:

Aromatic compounds, which contain a closed conjugated system and consequently possess considerable stability, are characterized by electrophilic substitution reactions. The presence of elevated electron density on both sides of the ring protects it against attack by nucleophilic reagents and, conversely, facilitates attack by cations and other electrophilic species.

Electrophilic substitution reactions in aromatic compounds proceed in two stages. The First stage involves the disruption of aromaticity and the transition of one of the carbon atoms of the aromatic ring into an sp³-hybridized state. The Second Stage consists of the departure of a proton and the restoration of the energetically favorable aromatic structure.

As an example, let us consider the mechanism of halogenation and nitration of benzene.

The reaction of benzene with halogens takes place in the presence of catalysts such as AlBr₃ or FeCl₃ (so-called Lewis acids). They induce polarization of the halogen molecule, after which it attacks the π-electrons of the benzene ring:

Initially, a σ-complex is formed, which slowly converts into a π-complex (note: σ-complex transitioning into an intermediate where bromine forms a covalent bond with one of the carbon atoms at the expense of two of the six electrons of the aromatic ring). The σ-complex is a less favorable structure due to the disruption of aromaticity, which is subsequently restored by the release of a proton.

The nitration of benzene is carried out using a mixture of nitric and sulfuric acids. Sulfuric acid catalyzes the reaction by protonating nitric acid, which then dissociates to form the nitronium ion - NO₂⁺:

The nitronium cation (NO₂⁺) attacks the aromatic ring, yielding a nitro derivative (in this case, nitrobenzene):

The reactions examined are characteristic not only of hydrocarbons, but also of hydrocarbon radicals in various classes of organic compounds. Furthermore, the reactivity and regioselectivity of these processes are significantly influenced by the electronic effects of substituents. Substituents with positive electronic effects that increase electron density in the radical facilitate the course of electrophilic reactions.

In the propylene molecule, the presence of the +I effect of the methyl group leads to the appearance of partial charges on the carbon atoms. The electrophilic species attacks the carbon atom bearing the partial negative charge:

In propenoic acid, due to the -I and -M effects of the carbonyl group, the electron density in the radical is decreased; therefore, addition reactions proceed with more difficulty than in Ethylene. In accordance with the electron density distribution in the radical, the electrophilic reagent interacts with the second carbon atom:

The formation of carbocations can occur via The addition of a proton at the site of π-bond cleavage. Consequently, catalysts for such electrophilic reactions

are frequently acids. An example of such reactions is the hydration of unsaturated compounds:

A water molecule adds to the resulting carbocation via the lone electron pairs of the oxygen atom. An unstable oxonium derivative is formed, which stabilizes through the elimination of a proton. The reaction products are alcohols.

The electronic effects of substituents determine the orientation of electrophilic substitution reactions in the aromatic ring. When studying these reactions, it was observed that if the ring already contains a substituent, subsequent substituents are directed to specific positions depending on the Nature of the first group. Groups such as -OH, -NH₂, alkyl radicals, and halogens predominantly direct incoming substituents to the ortho and para positions. They are classified as first-Class substituents:

Second-class substituents: -NO₂, >C=O, -COOH predominantly direct incoming substituents to the meta position:

Moreover, the bromination of phenol occurs more easily, while that of nitrobenzene is more difficult compared to benzene. To elucidate the causes of this differing directing effect of substituents, let us examine their electronic effects:

Hydrocarbon radicals increase electron density in the ortho and para positions via the +I effect. As noted in the Discussion of the reaction mechanism, the process begins with the Addition of an electropositive species, which will be directed toward the atoms possessing elevated electron density.

In the hydroxyl group, the mesomeric effect predominates because the valence electrons of Carbon and Oxygen reside in 2p-orbitals, between which effective orbital overlap occurs. In this case, the electron density within the ring increases, activating it at the ortho and para positions.

In chlorine, the inductive effect predominates because its valence electrons are located in the more diffuse 3p-orbital, and its overlap with the carbon 2p-orbital is less effective. Therefore, chlorine deactivates the benzene ring, although it still acts as an ortho/para-director due to a certain degree of p-π conjugation between the electrons of carbon and chlorine.

The nitro group exhibits both -I and -M effects and thus deactivates the ring, predominantly at the ortho and para positions. Since the attack of the electrophilic species takes place at the site of highest electron density, in this case, electrophilic substitution reactions will yield predominantly meta-isomers.

3. The oxygen atom of the hydroxyl group is the most electronegative in alcohol molecules. This causes a shift of the covalent bond electrons toward the oxygen atom and the polarization of these bonds:

The polarity of the O-H bond in the hydroxyl group of an alcohol dictates its ability to undergo heterolytic cleavage with the release of a proton, thereby exhibiting acidic properties. This occurs during interaction with active metals;

consequently, solid substances that dissolve in the alcohol are formed—alcoholates (alkoxides) featuring an ionic oxygen-metal bond:

The positive inductive effect of the hydrocarbon radical decreases the polarity of the O-H bond and weakens the acidic properties of alcohols. Therefore, alcohols are weaker acids than water (pK_a of water is 15.7, methanol is 16, ethanol is 18). For this same reason, acidity decreases with an increase in the number of carbon atoms in the radical. The acidity of polyhydric alcohols is higher than that of monohydric ones due to the -I effect of the hydroxyl groups (pK of ethylene glycol is 15.18). Hydrogen atoms of the hydroxyl groups in polyhydric alcohols are particularly easily substituted by certain heavy metals via the formation of inner-complex compounds, known as chelates:

Chelates possess vivid coloration, and their formation is utilized for the qualitative detection of polyhydric alcohols.

The polarity of the C-O bond in alcohol molecules governs their ability to participate in Nucleophilic substitution reactions, in which the hydroxyl group is replaced by another nucleophilic species.

Many nucleophilic substitution reactions in alcohols are acid-catalyzed. In this case, the first step involves proton addition due to the lone pair of electrons on the oxygen atom:

The resulting oxonium derivative exists in equilibrium with a carbocation:

This carbocation is stabilized through interaction with a nucleophilic species. For instance, when alcohols react with hydrogen halides, the carbocation interacts with the halide anion:

The Introduction of a halogen atom into a hydrocarbon molecule confers high biological activity upon the halogenated product. Haloalkanes are characterized by high anesthetic activity, which is why some of them are used as anesthetics. A halogen atom in the side chain of a benzene homologue imparts lachrymatory properties to the compound; for example, benzyl iodide C₆H₅-CH₂-I acts as a "police gas".

Iodoform CHI₃ is an antiseptic used in ointments, dusting powders, and dentistry.

Chloroethyl C₂H₅-Cl is used topically; it boils at 12⁰C–14⁰C and provides local anesthesia as it evaporates from the Skin surface.

Chloroform CHCl₃ is an inhalation anesthetic agent.

Fluorotan CF₃-CHClBr is a combined inhalation anesthetic agent.

Trichlorethylene Cl₂C=CHCl is used for short-term anesthesia.

During ether formation in the presence of sulfuric acid, the carbocation adds to the oxygen atom of another alcohol molecule, forming a disubstituted oxonium derivative:

which, upon losing a proton, is converted into an ether:

In alcohols, nucleophilic substitution reactions compete with elimination reactions. Thus, heating alcohols with concentrated sulfuric acid leads to dehydration and the Formation of Unsaturated hydrocarbons:

The main difference between ether-forming reactions and those yielding unsaturated hydrocarbons is that in the latter case, a larger amount of acid is used, which is sufficient to protonate all alcohol molecules. Under these conditions, carbocations cannot add to alcohol molecules; instead, they are stabilized by releasing a proton:

Alcohols containing a hydroxyl group attached to an sp²-hybridized carbon atom are highly unstable and convert into carbonyl compounds:

This is explained by the conjugation of the lone pair electrons of the oxygen atom with the electrons of the π-bond in the radical, as a result of which the hydroxyl group exhibits a +M effect. The electron density deficiency on the oxygen atom increases, leading to enhanced polarization of the O-H bond and increased mobility of the hydroxyl hydrogen. It is readily eliminated as a proton and, via the π-bond electrons, adds to the carbon atom bearing a partial negative charge.

The oxidation of alcohols yields various products depending on The structure of the alcohol. Primary alcohols are oxidized to aldehydes, and secondary alcohols to ketones:

During biological dehydrogenation, oxygen-containing compounds can release either two protons and two electrons, or a proton and a hydride ion:

This process proceeds with the participation of the coenzyme NAD⁺, which acts as a hydride ion acceptor.

Phenols are stronger acids than alcohols; the pK of phenol is 10.0, which is 6 units lower than the pK of aliphatic alcohols. This is attributed to the Displacement of the oxygen atom's lone pair electrons toward the aromatic ring (+M effect), which causes an increase in the polarization of the O-H bond and facilitates its heterolytic cleavage:

Unlike alcohols, phenols readily react with alkalis to form salts known as phenolates:

By increasing the electron density within the benzene ring, the hydroxyl group facilitates electrophilic substitution reactions and acts as an ortho-, para-directing group:

The participation of the hydroxyl oxygen atom in the formation of a closed conjugated system results in strengthening the bond between this atom and the carbon atom of the aromatic ring. Consequently, the hydroxyl group of phenols is resistant to nucleophilic substitution reactions. It is impossible to directly convert phenols into the corresponding halogenated hydrocarbon derivatives.

The hydroxyl group of phenols can be oxidized to a carbonyl group. The interconversion of hydroquinone and quinone is of great biological importance:

Quinones possess a conjugated system consisting of two π-bonds in the ring and two more in the carbonyl groups. The transformations described above do not involve the cleavage of the conjugated system, and therefore they do not require significant energy input and proceed quite readily.

The quinoid moiety is a structural component of coenzyme Q (ubiquinone). In the organism, ubiquinone is readily and reversibly reduced to the corresponding hydroquinone, which accounts for its Participation in the mitochondrial Respiratory Chain.

4. The chemical properties of nitrogen-containing compounds are largely determined by the presence of a lone electron pair on the nitrogen atom, which enables the formation of a dative covalent (coordinate) bond. Thus, when aliphatic amines are dissolved in water, a proton is added, while hydroxyl ions give the solution an alkaline reaction:

The reaction of amines with acids yields salts:

Due to the +I effect of hydrocarbon radicals, amines are stronger bases than ammonia.

The Basic Properties of aromatic amines are much weaker than those of aliphatic amines. This is due to the conjugation of the unshared electron pair of the nitrogen atom with the $\pi$-electron System of the aromatic ring (+M effect).

As a result, the electron density on the nitrogen atom decreases, and its ability to accept a proton is weakened. Aromatic amines in aqueous solution do not change the color of indicators and do not form salts with weak acids. When interacting with strong acids, salts are formed:

Electron-withdrawing substituents decrease the basicity of aromatic amines, whereas electron-donating substituents increase it.

Due to the unshared electron pair on the nitrogen atom, not only protonation can occur, but also interaction with compounds containing a carbon atom with a partial positive charge. Reactions with alkyl halides lead to the alkylation of amines:

This yields a salt from which alkalis liberate the free amine:

Thus, a primary amine can be converted into a secondary amine, and subsequently into a tertiary amine.

Complete the tasks and check your solutions against the answer keys

Task No. 1

1. What type of reaction is this:

A. Radical substitution.

B. Electrophilic addition.

C. Electrophilic substitution.

2. The methyl group in the toluene molecule exhibits The properties of:

A. Saturated hydrocarbons.

B. Unsaturated hydrocarbons.

C. Aromatic hydrocarbons.

3. Benzene is characterized by reactions of:

A. Radical substitution.

B. Electrophilic addition.

C. Electrophilic substitution.

Answer keys: 1-A, 2-A, 3-C.

Task No. 2

1. How do the acidic properties change in the series of compounds:

2.

A. Decrease.

B. Increase.

C. Remain unchanged.

2. Acidic properties of phenols compared to alcohols:

A. Decrease. B. Increase. C. Remain unchanged.

3. Nitro group (-NO₂; electron-withdrawing substituent):

A. Enhances acidic properties.

B. Weakens acidic properties.

C. Has no effect.

Answer keys: 1-B, 2-B, 3-A.