Reactive intermediate and free radicals.pdf

CARBOCATION: Carbocations in organic chemistry are defined as the chemical species that carries a positive charge on the carbon with only six valence electrons. It was known as carbonium ion. Since the carbon in carbocations has only six electrons, it i...

CARBOCATION: Carbocations in organic chemistry are defined as the chemical species that carries a positive charge on the carbon with only six valence electrons. It was known as carbonium ion. Since the carbon in carbocations has only six electrons, it is electron deficient; and therefore, acts as an electrophile in chemical reactions. CLASSIFICATION OF CARBOCATION The different carbocations are named based on the number of carbon groups bonded to the carbon. METHYL CARBOCATION: when no carbon is attached to the carbon with the positive charge. PRIMARY CARBOCATION: when one carbon is attached to the carbon with the positive charge. SECONDARY CARBOCATION: when two carbon is attached to the carbon with the positive charge. TERTIARY CARBONATION: when three carbon is attached to the carbon with the positive charge. ALLYLIC CARBOCATION: it is a carbon with a positive charge next to the carbon-carbon double bond. VINYLIC CARBOCATION: it is carbon with the positive charge attached to a double bond. ARYL CARBOCATION: it is carbon with positive charge and is part of a benzene ring. BENZYLIC CARBOCATION: it is the carbon with positive charge is immediately next to a benzene ring. GENREATION OF THE CARBOCATION The heterolytic cleavage of the covalent bond is responsible for the generation of most of the carbocation species. Some reactions involving the production of carbocations are given. i) Ionization of alkyl halides in polar solvents: ii) Protonation of alcohols followed by dehydration: iii) Protonation of unsaturated systems:  iv) Action of super acids on alkyl fluorides: v) Deamination of primary aliphatic amines by nitrous acid: STRUCTURE OF CARBOCATIONS: The carbon with a positive charge is in sp2 hybridization with three hybrid orbitals oriented at 120° in a plane with an empty pz orbital at the perpendicular and its shape is trigonal planar. There is also a vacant p orbital which indicates its electron-deficient nature. The carbon has 6 electrons in its valence shell. Due to this, it is an electron-deficient species, also known as an electrophile.  STABILITY OF CARBOCATIONS: Since the carbon in carbocations has only six electrons, it is electron deficient; and therefore, any effect that can compensate for the deficiency will stabilize the carbocation. i) Stability of alky carbocations based on inductive effect: Since the alkyl group has an electron donating effect (+I), the stability of the carbocation will increase as the number of donating abilities of the attached group increases. The stability order of alky carbocations since inductive effect is given below. tertiary > secondary > primary > methyl ii) Stability of alky carbocations on the basis of hyperconjugation. The existence of the hyperconjugation effect can be used to rationalize. Hence, as far as the number of possible hyper-conjugative structures possible is concerned, tertiary carbocation should be more stable than secondary, which in turn should be more stable than primary. REACTIVITY OF CARBOCATIONS: The principal routes by which the carbocations can react to give rise to stable products are given below. i. Nucleophilic attack: In these types of reactions, a carbocation may combine with a species by accepting an electron pair. Furthermore, it should also be noted that if all the three groups on the carbocation are different, a racemic mixture will be obtained. ii. Proton removal: In these types of reactions, carbocation may result in the removal of a proton from the adjacent atom forming a double bond. iii. Rearrangement reaction: 1-2 methyl shit or 1-2 hydride shifts are very common in carbocation chemistry to attain a more stable counterpart. For instance, a primary carbocation will prefer to rearrange itself into a more stable tertiary carbocation. iv. Addition reactions: A carbocation may attack at the triangular face of a double bond to create a new positively charged center as shown below. CARBANIONS The chemical species that carries a negative charge on the carbon with only eight valence electrons. Since the carbon in carbanions has its octet complete, it is electron-rich; and therefore, acts as a nucleophile in chemical reactions. GENERATION OF CARBANIONS: The heterolytic cleavage of the covalent bond is responsible for the generation of most of the carbanion’s species. Some reactions involving the production of carbanions are given. i) Hydrogen abstraction by a strong base from the carbon alpha to cyano, nitro, or carbonyl groups: ii) Nucleophilic addition to α, β-unsaturated species: iii) Abstraction of terminal hydrogen from acetylene:  STRUCTURE OF CARBANIONS: It has been experimentally found that the carbanions are trigonal pyramidal around the carbon bearing negative charge. Now valence bond theory, as well as molecular orbital theory, easily accounted for such structure, it is more comfortable to discuss the valence bond approach. The carbon with a negative charge is in sp3 hybridization with three hybrid orbitals forming bonds and the fourth hybrid orbital containing lone pair of electrons. Furthermore, it should also be kept in mind that if the carbon bearing negative charge is adjacent to multiple bonds, the carbanions will adopt a planar structure to get stable by dispersing the negative charge. STABILITY OF CARBANIONS: The carbon in carbanions has eight valence electrons, it is electron-rich; and therefore, any effect that can compensate the electron density accumulation will stabilize the carbanions. i. Stability of alky carbanions based on inductive effect: Since the alkyl group has an electron donating effect (+I), the stability of the carbocation will increase as the number of donating abilities of the attached group increases. The stability order of alky carbocations based on inductive effect is given below. ii. Stability of carbanions based on hybridization:  The nature and type of hybridization effect can be used to rationalize the relative stability of different carbanions as shown below. Hence, we can say that as the s-character of carbon bearing negative charge increases, the lone pair gets better stabilization; and therefore, overall carbanionic stability also increases. REACTIVITY OF CARBANIONS: The principal routes by which the carbanions can react to give rise to stable products are given below. i) Lone pair donation: One of the most common pathways of carbanions reaction is the donation of electrons to a positive species like proton, or some species with an empty orbital. ii. Associative reaction: The carbanions can bond with a tetra coordinated carbon followed by displacement of one of the previously attached groups. iii. Rearrangement reaction: Like Carbocation the carbanions can also undergo rearrangement reaction although it is not very common. iv. Addition reactions: A carbonation may attack at the triangular face of a double bond to create a new negatively charged center as shown below.  CARBENES: The term carbenes are the chemical species that carries two non-bonding electrons (paired or unpaired) on the carbon with a total of six valence electrons. Since the carbon in carbenes has only six electrons, it is electron deficient; and therefore, acts as an electrophile in chemical reactions. GENERATION OF CARBENES: Some of the most common pathways involving the production of carbenes are given below. i. Decomposition of ketones or diazoalkanes: ii. Thermal or photolytic cleavage of cyclopropanes and oxiranes: iii. Attack of strong base on chloroform: STRUCTURE OF CARBENES: Carbenes can be classified based on the distribution of non-bonding electrons. There are primarily two types carbenes: i. singlet carbenes. ii. triplet carbenes.  i. SINGLET CARBENES. It has been experimentally found that the singlet carbenes are V-shaped and are derivatives of trigonal planar geometry. The central carbon is in sp2 hybridization with three hybrid orbitals oriented at 120° in a plane; two half-filled orbitals participating in bonding while the third hybrid orbital contains the lone pair. The pz orbital remains empty and is perpendicular to the molecular plane. ii. TRIPLET CARBENES. The triplet carbenes are either linear or V- shaped (depending upon the reaction requirement). The central carbon in linear triplet carbene is in sp hybridization with two hybrid orbitals oriented at 180o along z-axis participating in bonding; whilst the atomic orbital px and py contain unpaired electrons. The central carbon in bent triplet carbene is in sp2 hybridization with three hybrid orbitals oriented at 120° in a plane; two half-filled orbitals participating in bonding whilst the third hybrid orbital contains an unpaired electron. The other unpaired electron is in the atomic pz orbital perpendicular molecular plane. STABILITY OF CARBENES: In the case of simple hydrocarbons, triplet carbenes typically have energies 8 kcal/mol less than singlet carbenes due to Hund's rule of maximum multiplicity; and therefore, we can conclude that the triplet is the ground state and singlet one is the excited state entities. Also, groups that can donate electron pairs can stabilize the singlet carbene by delocalizing the pair into an empty pz orbital. Furthermore, the singlet state can become the ground state if its energy is significantly reduced. However, triplet carbenes cannot be stabilized by this strategy. A carbene 9-fluorenylidene is found to exist in a rapid equilibrating mixture of triplet and singlet states with an energy difference of roughly 1.1 kcal/mol. Nevertheless, it is disputed if diaryl carbenes like fluorene carbene are true carbenes since the electrons can be delocalized to such a level that they become biradicals in nature. Experimental studies have suggested that triplet carbenes can be stabilized thermodynamically with heteroatoms of electropositive nature (like in silyl and silyloxy carbenes). REACTIVITY OF CARBENES: The principal routes by which the carbenes can react to give rise to stable products are given below. i. ADDITION REACTIONS. Besides the carbon-carbon double bonds including aromatic systems), carbenes may also add to carbon heteroatom multiple bonds. ii. INSERTION REACTION: In these reactions, carbenes get inserted into CH bonds to give stable products. iii. DIMERIZATION REACTION: Carbenes may undergo dimerization to form an alkene; however, it is more likely to arise from the attack by a carbene on a molecule of a carbene precursor. iv. REARRANGEMENT REACTIONS: The carbenes can also undergo rearrangement reactions to yield very stable products as given below. v. FRAGMENTATION REACTIONS: many substitutions and elimination products are obtained from the fragmentation reactions of alicyclic oxychloro carbenes as given below. vi. REARRANGEMENT REACTIONS: Triplet carbenes are also able to abstract hydrogen or any other groups or atoms to yield free radicals products. NITRENES: The term nitrenes are the chemical species that carries four non-bonding electrons paired or unpaired) on the nitrogen with a total of six valence electrons. Since the nitrogen in carbenes has only six electrons, it is electron deficient; and therefore, acts as an electrophile in chemical reactions. GENERATION OF NITRENES: Some of the most common pathways involving the production of nitrenes are given below. i. Photochemical or thermal decomposition of isocyanates or azides: ii. Elimination of sulphonate ion from certain compounds.  STRUCTURE OF NITRENES: There are primarily two types of nitrenes: i. singlet nitrenes. ii. triplet nitrenes. i. singlet nitrenes. It has been experimentally found that singlet nitrenes are linear and are derivatives of trigonal planar geometry. The nitrogen is in sp2 hybridization with three hybrid orbitals oriented triangularly in a plane; one half-filled hybrid orbital participating in bonding with carbon whilst the second and third hybrid orbitals contain the lone pairs. The pz orbital remains empty and is perpendicular to the above-mentioned triangular plane. ii. triplet nitrenes. The triplet nitrenes are also linear. The nitrogen in triplet nitrenes is in sp hybridization with two hybrid orbitals oriented at 180° along the z-axis; one hybrid orbital (half-filled) participating in bonding whilst the other hybrid orbital contains a lone pair. The atomic px and py atomic orbital containing the unpaired electrons. STABILITY OF NITRENES: Although nitrenes are too reactive to isolate under normal conditions, in 2019, an authentic triplet nitrene was isolated by Betley and Lancaster, stabilized by coordination to a copper center in a bulky ligand. Furthermore, triplet nitrenes are thermodynamically more stable but react stepwise allowing free rotation and thus producing a mixture of stereochemistry. They are usually detected by adding carbon monoxide as it can form isocyanates with nitrenes which can be isolated easily.  REACTIVITY OF NITRENES: The principal routes by which the nitrenes can react to give to stable products are given below. i. ADDITION REACTIONS: Nitrenes may add to carbon-carbon multiple bonds to give rise to some stable products. ii. INSERTION REACTION: In these reaction nitrenes get inserted into CH bonds to give stable products. iii. DIMERIZATION REACTIONS: Nitrenes may undergo dimerization to form diamide. iv. REARRANGEMENT REACTIONS: The nitrenes can also undergo rearrangement reactions to yield very stable products as given below. v. HYDROGEN ABSTRACTION: Nitrenes are also able to abstract hydrogen or any other groups or atoms to yield free radicals’ as given below.  BENZYNES or ARYNE or DEHYDROBENZENE Benzynes are unsaturated hydrocarbons with a triple bond in a six-membered aromatic ring. Benzyne, also known as aryne, is a highly reactive organic molecule. It has not been isolated in its pure form but can be inferred by the stable molecules it produces. Its instability arises from its extremely strained triple bond. GENERATION OF BENZYNES: Benzyne is typically generated in situ (meaning it is formed within a reaction mixture) due to its reactivity. Some methods of benzyne formation are given below. i. From dehydrohalogenation of aryl halides: ii. Diazotization and neutralization of 2-diazoniobenzene-1-carboxylate. iii. Cycloaddition of 1,3-diyne and alkyne  STRUCTURE OF BENZYNES: Benzyne has a hexagonal planar structure in which 6 π-electrons are found above and below the ring, which are delocalized, and two additional electrons are found in the extra π-bond outside the ring formed because of the lateral overlap of two sp2 hybrid orbitals. in benzyne, the triply bonded carbon is attached to the ring carbon, due to which it is not possible to be linear even if it is sp hybridized and thus the C–C≡C bond angle becomes less than 180° (Between 120° to 180°), because of which the deformation of the bond angle is generated in the benzyne ring. Due to the deformation of the bond angle, angle strain is generated in the benzyne and thus benzyne becomes a highly reactive species. The strain energy of benzyne is about 50 kcal/mol which is more than the strain energy of cyclopropane (20 kcal/mole). Hybridization of carbon atoms in benzyne ring The Benzyne ring contains six carbons, out of which four doubly bonded carbon atoms are sp2 hybridized while two triply bonded carbon atoms are sp hybridized. Bond lengths are also changed due to asymmetry in hybridization. Thus, the asymmetry present in benzyne makes it unstable and reactive. Aromaticity of benzyne The resonating structures of benzyne show that only three double bonds of the ring participate in delocalization. Thus, it obeys Huckel’s (4n+2) π rule, making benzyne an aromatic compound.  STABILITY OF BENZYNE: Benzyne’s instability stems from its strained structure, which includes an extra bond between two ortho carbons. It lacks the full aromatic stabilization that benzene possesses due to the missing hydrogen atoms. Consequently, benzyne readily reacts with any available nucleophile (such as the solvent or other reagents) to form additional products. Benzyne’s existence is inferred from the stable molecules it produces, as it has not been directly isolated. Its instability arises from its extremely strained triple bond. REACTIVITY OF BENZYNES: Benzyne reacts rapidly with any available nucleophile. For instance, when benzyne encounters a solvent like ammonia, it forms an addition product. The rearrangements in these reactions result from the attack of the nucleophile at one of the carbons in the extra bond of the intermediate. Some of the reactions of benzynes are given below. i. Nucleophilic additions to arynes: benzyne forms addition products, usually by nucleophilic addition and protonation. ii. Aryne coupling: Aryne coupling reactions allow for generation of biphenyl compounds which are valuable in pharmaceutical industry and agriculture. iii. Cyclic product formation: Aryne reacts with a diene to form a cyclic product.  TYPES OF ORGANIC REACTIONS: Organic reactions may be classified into four main types. i. Substitution Reactions. ii. Addition Reactions. iii. Elimination Reactions. iv. Rearrangement Reactions. i. SUBSTITUTION REACTION: A reaction in which a part of one molecule is replaced by other atom or group of atoms without causing a change in the rest of the molecule is called substitution reactions. A hydrogen atom of methane is replaced or substituted by chlorine atom. The substitution reactions may be brought about by free radicals’ nucleophile or electrophile reagents. Thus, there are free radical substitution reactions, nucleophilic substitution reaction and electrophilic substitution reactions. ii. ADDITION REACTIONS: - When two molecules of same or different substances combine giving rise to a new product is called addition. In these reactions atom or groups of atoms are simply added to a double or triple bond without the elimination of any atom or other molecules.  Addition reactions may be free radical addition, Nucleophilic and Electrophilic additions reaction. iii.ELIMINATION REACTION: - Those reactions involve the removal of atoms or groups of atoms from a molecule to form new compounds containing multiple bonds are called elimination reactions. Dehydro-halogenation of alkyl halides is a common example of this type of reactions. Hydrogen and halogen atoms are removed resulting in the formation of double bond. Similarly, dehalogenation of alkyl halides also results in the formation of multiple bonds.  The dehydrogenations of alkenes also give alkyne resulting in the formation of triple bond. So, elimination reactions always produce unsaturation in the molecules. Elimination reactions are the opposite of addition reactions. iv. REARRANGEMENT REACTION: Those reactions which involve the migration of an atom or a group of atoms from one atom to the other atom within the same molecule. The product is always the structural isomer of the original compound. It is interesting to note that the first organic compound urea was synthesized in the laboratory by Wohler involved a rearrangement reaction. Similarly, maleic acid when heated in a sealed tube is converted into fumaric acid through rearrangement reaction.  Free radicals: Free radical: The term free radicals are defined as the chemical species that carries odd or unpaired electrons on the carbon with only seven valence electrons. Or a radical (more precisely, a free radical) is an atom, molecule, or ion that has unpaired valence electrons or an open electron shell. Since the carbon in free radicals has only seven electrons, it is electron deficient; and therefore, acts as an electrophile in chemical reactions. Generation of free radicals: The homolytic cleavage of the covalent bond is responsible for the generation of most of the free radicals species. Some reactions involving the production of free radicals are given below. i. Thermal cleavage: ii. Photochemical Cleavage:  STRUCTURE OF FREE RADICALS: It has been experimentally found that the free radicals are trigonal planar around the carbon bearing odd electron. Now valence bond theory, as well as molecular orbital theory, easily accounted for such structure, it is more comfortable to discuss the valence bond approach. The carbon with the odd electron is in sp2 hybridization with three hybrid orbitals oriented at 120° in a plane perpendicular to pz orbital occupied by the odd electron. STABILITY OF FREE RADICALS: The carbon in free radicals has only seven electrons, it is electron deficient; and therefore, any effect that can compensate for the deficiency will stabilize the carbocation. i) Stability of alky free radicals based on inductive effect: Since the alkyl group has an electron-donating effect (+I), the stability of the free radicals will increase as the number of donating groups attached increases. The stability order of alky free radicals based on inductive effect is given below. ii) Stability of alky free radicals based on hyperconjugation: The existence of the hyperconjugation effect can be used to rationalize the relative stability of different free radicals as shown below.  Hence, as far as the number of possible hyper-conjugative structures possible is concerned, tertiary free radicals should be more stable than secondary, which in turn should be more stable than primary. iii) Stability of ally and benzyl free radicals: The stability of the free radicals in which the carbon bearing odd electron is adjacent to the double or triple bond can be rationalized in terms of resonance effect. First, let us draw the resonance structures of allyl and benzyl free radicals. Now, as the number of phenyl groups attached to carbon bearing electron increases, the number of resonating structures will also increase, and hence the stability. Therefore, the expected order of the stability of unsaturated systems with carbon bearing odd electron should be as given below.  REACTIVITY OF FREE RADICALS: The principal routes by which the free radicals can react to give rise to stable products are given below. i. Decomposition reactions: One of the most common examples of this type of process is the decomposition of the benzoxy radical. ii. Hydrogen abstraction: In these types of reactions, a free radical may result in the removal of a proton from the same (intermolecular process) or another molecule (intramolecular process). iii. Rearrangement reaction: Free radicals may undergo rearrangement reactions to yield different but stable free radical counterparts. iv. Addition reactions: The free radical obtained from an alkene may attack the triangular face of the double bond of another alkene molecule, and the process continues to yield polymers.  FREE RADICAL SCAVENGERS: Substances that chemically inhibit the oxidation process are called free radical scavengers. They are also known as antioxidants. For appropriate physiological function, it is necessary to have a proper balance between free radicals and free radical scavengers (antioxidants). These remarkable compounds interact with and neutralize free radicals, preventing them from causing damage. our bodies produce some antioxidants naturally (called endogenous antioxidants), but we also rely on external sources, primarily our diet, to obtain the rest. Fruits, vegetables, and grains are rich in dietary antioxidants. Examples include beta- carotene, lycopene, and vitamins A, C, and E (also known as alpha-tocopherol). Additionally, the mineral element selenium contributes to antioxidant effects through proteins containing this essential component. SCAVENGING Scavenging is a process in which specific molecules help us to protect ourselves from the damage caused by the free radicals. Antioxidants act as radical scavengers. Examples of antioxidants which scavenge free radicals are phenolic compounds, ligands, flavonoids, and phenolic acids. i. Antioxidants react with transition metals to form complexes and thus avoid the catalytic effect of the metals in the oxidation process. ii. Antioxidants that decompose peroxides and produce stable substances which are unable to produce radicals such as selenium containing glutathione peroxidase, an antioxidative enzyme which inactivate free radicals and other oxidants, particularly hydrogen peroxide. iii. Antioxidants which inactivate the singlet form of oxygen, In the presence of photosensitizers such as chlorophyll and pheophytins, singlet oxygen may be formed from ordinary triplet oxygen by the action of light. iv. Antioxidants prevent the enzymatic activity required for auto-oxidation. Examples are flavonoids, phenolic acids and gallates which deactivate the lipoxygenase. v. Methane is used to scavenge Chlorine free radicals in the atmosphere. Applications of free radicals scavengers: 1. Health and Disease Prevention: i. Oxidative Stress Management: Antioxidants combat free radicals produced in the body due to intrinsic (metabolic processes) and extrinsic (pollution, smoking, UV radiation) factors. They prevent oxidative stress, which can disrupt normal body physiology and lead to diseases like cancer, Alzheimer’s, and diabetes. ii. Endogenous and Exogenous Antioxidants: Our bodies produce endogenous antioxidants, while exogenous antioxidants obtained from external sources fulfill dietary requirements. iii. Plant-Derived Antioxidants: Plants are rich sources of antioxidants. Their safer use, variety, and dosage are explored for treating life-threatening diseases. iv. Role in Neurodegenerative Disorders:  Antioxidants play a crucial role in managing conditions like Alzheimer’s and other neurodegenerative disorders. 2. Industrial Applications: i. Food Industry: Antioxidants are used as food additives to prevent food deterioration caused by exposure to oxygen and sunlight. Dark storage and proper packaging help preserve food. ii. Cosmetics Industry: Antioxidants contribute to skincare products, protecting against oxidative damage and promoting healthy skin. iii. Pharmaceuticals: Antioxidant nanoparticles are employed as a therapeutic strategy against oxidative stress. iv. Nanotechnology: Nanoparticles find applications in various industries, including pharmaceuticals, cosmetics, and food production. In summary, antioxidants play a vital role in maintaining health, preventing diseases, and preserving various products across different sectors.