Module 3 EC Organic Chemistry PDF

Winter semester 2023-24 Module-3 Organic intermediates and reaction transformations Contents…. (6 h) Organic intermediates - stability and structure of carbocations, carbanions and radicals (2 h) Aromatics - (aromaticity including...

Winter semester 2023-24 Module-3 Organic intermediates and reaction transformations Contents…. (6 h) Organic intermediates - stability and structure of carbocations, carbanions and radicals (2 h) Aromatics - (aromaticity including heterocycles) (2 h) Organic transformations for making useful drugs for specific disease targets (two examples) and dyes (two examples) (2 h) 1 An intermediate is a molecular species that is formed from two or more reactants and then reacts further to give the products. These specific organic intermediates are short- lived (10-6 second to a few seconds only). They are ready to convert into more stable molecules. Among all, carbenes and carbocations are relatively stable. Only carbanions have a complete octet around the carbon. 2  Carbocations Organic species having a positively charged carbon atom bearing only six bonded electrons are called carbocations. For example: Structure: ❖ The carbon atom with a positive charge is referred as carbocation and it belongs to sp2 hybridization. ❖ The three sp2 hybridized orbitals are utilized in making bonds to three substituents. ❖ In order to minimize repulsion between the bonding electron pairs (i.e. to afford maximum separation of these electron pairs) a carbocation possesses a planar configuration with bond angles of 120o. The empty p orbital is perpendicular to the plane. ❖Carbocations are extremely reactive species due to their ability to complete the octet of 3 the electron-deficient carbon.  Classification of Carbocations Carbocations are classified as primary (1o), secondary (2o), and tertiary (3o) on the basis of number of carbon atoms (one, two, or three) directly attached to positively charged carbon. For example: The factors responsible for carbocation stability are – (i) Inductive effect, (ii) Hyperconjugative effect, (iii) Resonance effect, (iv) Steric effect and (v) Constituting an aromatic system. (i) Inductive effect ❖ A charge-dispersing factor stabilizes an ion. ❖ The electron-releasing inductive effect (+I) exerted by an alkyl group attached to the positive carbon of a carbocation neutralizes the charge partially. ❖ As a consequence, the charge becomes dispersed over the alkyl groups and the system becomes stabilized. ❖ For example, the methyl groups in isopropyl cation stabilize the system through their +I effects. ❖ The stability of carbocations increases with increasing the number of alkyl groups attached to the 4 positive carbon. (ii) Hyperconjugative effect ❖ An alkyl group may reduce the positive charge of a carbocation by hyperconjugative electron- release. ❖ The charge becomes dispersed over the α-hydrogens and consequently, the system becomes stabilized. Hyperconjugation in ethyl cation, for example, occurs as follows ❖ As the number of α-hydrogens, i.e., the number of hyperconjugative forms increases, the stability of carbocations increases. Hence, the order of stabilities of methyl substituted carbocations is :: (iii) Resonance effect ❖ Resonance is a major factor influencing the stability of carbocations. ❖ When the positive carbon of a carbocation is next to a double bond, effective charge delocalization with consequent stabilization occurs. ❖ Allyl and benzyl cations, for examples, are found to be highly stabilized by resonance. 5  (iv) Steric effect ❖ Steric effect causes an increase in stability of tertiary carbocations having bulky alkyl groups. ❖ For example, the substituents in tri-isopropyl cation (having planar arrangement with 120° angles) are far apart from each other and so there is no steric interference among them. ❖ However, if this carbocation is added to a nucleophile, i.e., if a change of hybridization of the central carbon atom from sp2 (trigonal) to sp3 (tetrahedral) takes place, the bulky isopropyl groups will be pushed together. ❖ This will result in a steric strain (B strain) in the product molecule. Because of this, the carbocation is much reluctant to react with a nucleophile, that is, its stability is enhanced due to steric reason. (v) Constituting an aromatic system ❖ The vacant p orbital of a carbocation may be involved in constituting a planar (4n +2)π electron system. where n = 0,1,2.... etc., i.e., a carbocation may be stabilized by constituting an aromatic system. ❖ Cycloheptatrienyl cation, for example, is unusually stable because it is a planar 6π electron system and aromatic. 6 Reaction of Carbocations Question: Arrange the following carbocations in order of their increasing stability and provide reason. ❖ The carbocation I is stabilized by the +I effects of three -CH3 groups and hyperconjugative effect involving nine C-H bonds. ❖ The carbocation III is similarly stabilized by +I effect of three ring bonds. ❖ However, it is not stabilized by hyperconjugation because formation of a double bond at the bridgehead position is not possible (Bredt's Hence, the order of their increasing stability is: rule). ❖ Again, the carbocation suffers from angle strain because the angle between bonds is somewhat less than the sp2 bond angle, i.e., 120". ❖ The carbocation II is the most stable one because it is highly stabilized by resonance and also by both inductive and hyperconjugative effects of two methyl groups. 10  Carbanions The species containing negatively charged carbon atom is known as carbanion. For example: Structure: ❖ The central carbon atom of a carbanion is sp3 hybridized. ❖ It is surrounded by three bonding pairs and one unshared pair of electrons which occupies an sp3 orbital. Thus, a carbanion is expected to have the tetrahedral shape. ❖ However, the shape is not exactly that of a tetrahedron. It is found to have the pyramidal shape. ❖ Since the repulsion between the unshared pair and any bonding pair is greater than the repulsion between any two bonding pairs, the angle between two bonding pairs (i.e., two sp3- σ bonds) is slightly less than the normal tetrahedral value of 109.5° and because of this, a carbanion appears to be shaped like a pyramid with the negative carbon at the apex and the three groups at the corners of a triangular base. ❖ However, the resonance-stabilized carbanions, such as allylic and benzylic carbanions are sp2 hybridized and they assume trigonal planar structure. 11 The factors responsible for carbanion stability are - The structural features responsible mainly for the increased stability of carbanions are : (i) the amount of ‘s’ character of the carbanion carbon atom, (ii) inductive electron withdrawal, (iii) conjugation of the non-bonding electron pair with an unsaturated system, and (iv) constituting an aromatic system. (i) The amount of ‘s’ character of the carbanion carbon atom ❖ An s orbital is closer to the nucleus than the p orbital in a given main quantum level and it possesses lower energy. ❖ An electron pair in an orbital having large s character is, therefore, more tightly held by the nucleus and hence of lower energy than an electron pair in an orbital having small s character. ❖ Hence, a carbanion at an sp hybridized (50% s character) carbon atom is more stable than a carbanion at a sp2 hybridized (33.33% s character) carbon atom, which in turn is more stable than a carbanion at an sp3 hybridized (25% s character) carbon atom. Thus, the order of carbanion stability is: (ii) Inductive electron withdrawal ❖ Groups having electron-withdrawing inductive effects (H) stabilize a carbanion by dispersing the negative charge. ❖ In a nitrogen ylide, for example, the carbanion is stabilized by the -I effect of the adjacent 12 positive nitrogen. (iii) Conjugation of a non-bonding electron pair with an unsaturated system ❖ Where there is a double or triple bond α to the carbanion carbon atom, the anion is stabilized by delocalization of its negative charge with the t orbitals of the multiple bond. ❖ Thus, allylic and benzylic carbanions and the carbanions attached to the functional groups such as -NO2, -C≡N, >C=O, etc. are stabilized by resonance. (iv) Constituting an aromatic system ❖ The unshared pair of a carbanion may be involved in constituting a planar (4n + 2)π electron system where n = 0, 1, 2... etc., i.e., a carbanion may be stabilized by constituting an aromatic system ❖ Cyclopentadienyl anion, for example. is unusually stable because it is a 6π electron system and aromatic. Question: Give the order of stability of the following simple carbanions : Because of the destabilizing influence of the electron-donating inductive effect of alkyl groups, the order of stability of these simple carbanions is as follows: 13 Reaction of Carbanions Reactions of Carbanions Question: Arrange the following carbanions in each of the following series in order of increasing stability: The order of increasing stability of these carbanions is: ❖ The electron-releasing methyl groups of isopropyl anion (I) intensify the negative charge on carbon and make it less stable than methyl anion (III) where there is no possibility of charge intensification. ❖ The external orbitals (orbitals directed to the outside bonds) in cyclopropane have larger (33%) s character i.e., they are approximately sp2 orbitals. Because of this, the unshared pair in cyclopropyl anion (IV) is more tightly held with the carbon nucleus than the electrons in methyl anion (III) that occupies an sp3 orbital (25% s character). Consequently, the former anion is more stable than the latter. ❖ In vinyl anion (VI), the unshared pair occupies an sp orbital (33.33% s character) and so this anion is somewhat more stable than cyclopropyl anion (IV). ❖ The charge in allyl anion (II) is delocalized by resonance with the adjacent double bond and so it is more stable than vinyl anion (VI) in which the charge is localized. ❖ Since the unshared pair in cyclopentadienyl anion (V) is involved in forming an aromatic system, charge delocalization and consequent stabilization is far greater for this anion than for allyl anion. 17  Radicals ❖ Homolytic cleavage of covalent bonds leads to the formation of neutral species possessing an unpaired electron. These are known as free radicals. ❖ Free radicals containing odd electrons on carbon atoms are collectively called carbon radicals or simply free radicals. For example, methyl radical (ĊH3 ), phenyl radical (Ph), etc. ❖ They are classified as primary, secondary, and tertiary free radicals according to the number of carbon atoms (one, two or three) directly attached to the carbon atom bearing the unpaired electron. ❖ For example, ethyl radical (CH3ĊH2) is a primary, isopropyl radical (Me2ĊH) is a secondary and tertbutyl radical (Me3Ċ) is a tertiary radical. Stability: (i) Hyperconjugation: Free radicals become stabilized by hyperconjugation involving α-H atoms ❖ As the number of -H atoms increases, hyperconjugation becomes more effective and consequently, the radical becomes more stabilized. ❖ The relative stability of simple alkyl radicals is found to follow the sequence (most stable) R3Ċ (tertiary) > R2ĊH (secondary) > RĊH2 (primary) > ĊH3 (methyl) (least stable). ❖ For example, tert-butyl radical, Me3Ċ (with nine hyperconjugable α-H atom) is more stable than isopropyl radical, Me2ĊH (with six hyperconjugable α-H atom) which in turn is more stable than ethyl radical, MeĊH2 (with only three hyperconjugable α-H atom). The methyl radical, ĊH3 is least stable because the unpaired electron is not18 at all delocalized. (ii) Resonance: ❖ Resonance is a major factor influencing the stability of free radicals. ❖ When the carbon bearing the odd electron is - to a double bond, effective delocalization of the unpaired electron with the π orbital system with consequent stabilization occurs. ❖ Allyl and benzyl radicals, for example, are found to be particularly stable because of resonance. (iii) Steric Strain: ❖ Another factor responsible for the increased stability of tertiary radicals is steric. ❖ There occurs considerable relief of steric strain when a sp2 hybridized tertiary radical is formed from an sp3 hybridized precursor and this is because repulsion between the bulky alkyl groups is relieved to a certain extent by an increase in bond angles from 109.5° to about 120°. ❖ Thus, the radical is much reluctant to react further, i.e., its stability is enhanced due to steric reason. 19 Reactions of Free Radicals  Aromaticity Aromaticity was associated with a specific chemical reactivity (substitution reactions in preference to addition). Aromaticity is now generally associated with the property of special stability of certain completely conjugated cyclic and planar molecules. A major contribution to the stability of aromatic systems comes from the delocalization of electrons (which also imparts diamagnetic ring current). Hückel molecular orbital (HMO) theory states that planar monocyclic completely conjugated hydrocarbons will be aromatic when the ring contains 4n+2 π electrons (Huckel’s Rule).  Criteria of Aromaticity Aromatic compounds are Rule 1: Always cyclic structures Rule 2: Each element of the ring should have overlapping p-orbitals which are perpendicular to the ring and imparts planarity to the molecule. Rule 3 : Delocalization is possible only if p orbitals can overlap efficiently which provides additional stability to the system. (delocalization energy or resonance energy). For example, cyclooctatetraene despite having alternate single and double bonds, do not show the extended overlap of p-orbitals and delocalization as it is a tub shaped. Rule 4: All the aromatic compounds obey the Huckel’s rule of (4n+2) 𝝅 electrons. Aromatic compounds: Molecules which obey all the 4 rules. Non-aromatic compounds: Molecules which follow these 4 rules partially i.e. non-cyclic, non-planar, or do not hold a comprehensive conjugated π system inside the ring. Anti-aromatic compounds: Exclusively do not follow Huckel’s rule. 4n+2 (n = 0)= 2 π electrons Cyclic Non Planar Not Conjugated Follow Huckel’s rule Non Aromatic Cyclic Planar Conjugated Follow Huckel’s rule Aromatic Stability Order: Aromatic > Nonaromatic > Antiaromatic  * 4n+2 (n = 1)= 6 π electrons Cyclic Planar Conjugated Follow Huckel’s rule Aromatic Cyclic Non Planar Non Conjugated Follow Huckel’s rule Cycloheptatriene Non Aromatic  * 4n+2 (n = 2)= 10 π electrons Cyclic Planar Cyclic Conjugated Non Planar Follow Conjugated Huckel’s rule Follow Huckel’s rule Aromatic Non aromatic * 4n+2 (n = 3,4)= 14 and 18 π electrons Cyclic Planar Conjugated Follow Huckel’s rule Aromatic * 4n (n=1) = 4 π electrons -Cyclic -Planar -Conjugated - Do not Follow Huckel’s rule Antiaromatic Cyclic Non Planar Non Conjugated Do not Follow Huckel’s rule Non aromatic  * 4n (n = 2)= 8 π electrons Cyclooctatetraene is more Cyclic flexible than Non Planar cyclobutadiene and it Conjugated assumes a non-planar ‘tub Do not Follow Huckel’s rule shaped’ conformation that nonaromatic due to non avoids most of the planarity overlapping between p- orbitals. * 4n (n = 3,4)= 12 and16 π electrons Cyclic Cyclic Planar Non Planar Conjugated Conjugated Do not Follow Huckel’s rule Do not Follow Huckel’s rule Antiaromatic non aromatic Aromatic Anti-aromatic Non-aromatic 29 Characteristics of 3-Membered Ring Heterocyclic Compounds Cyclic, Conjugated sp2 hybridised carbons 4 π elections ( 4n rule) Anti-aromatic Cyclic no conjugated sp2 hybridised carbons Non-aromatic 30  Aromaticity of 4-Membered Ring Heterocyclic Compounds While counting the number of π- electrons, first count the electrons Cyclic which are delocalized over the ring. In this case, nitrogen lone pair is ≡ Conjugated sp2 hybridised carbons localised in an sp2 orbital (red) which 4 π elections ( 4n is orthogonal to the π system (blue) rule) and does not participate in Anti-aromatic resonance. Non-aromatic Cyclic no conjugated sp2 hybridised 2H-OXETEN 2H-THIETEN carbons 31 Five Membered Heterocycle: Pyrrole 32  Six Membered Heterocycle: Pyridine Pyridine replaces the CH of benzene by an N atom with a lone pair of electrons and hybridization is sp2 with similar resonance stabilization energy. Lone pair of electrons does not involve in aromaticity. Pyridine is a weak base. Pyridine is π-electron deficient. Electrophilic aromatic substitution is difficult. Nucleophilic aromatic substitution is easy. Resonance energy of some of the aromatic systems Fused Heterocyclic Compounds Aromatic due to 10 π-electrons Benzene part is non-reactive Electrophilic aromatic substitution occurs at the 3-position. Model Questions 34  Synthetic Route of Aspirin In the year of 1897, Bayer laboratory gave acetyl salicylic acid the name of Aspirin. Aspirin is one of the safest and most effective medicines and is extensively used medications globally, which is displayed on the WHO’s List of Essential Medicines. Mechanism of Aspirin Synthesis Synthesis of aspirin is an esterification reaction of salicylic acid and acetic anhydride with an acid catalyst (sulfuric or phosphoric acid). Uses of Aspirin/Acetylsalicylic acid-(C9H8O4) ❖ Used as an inhibitor of cyclooxygenase, in the treatment of different types of headaches and to prevent venous and arterial thrombosis. ❖ Useful as an anti-inflammatory agent for long-term as well as acute inflammation; gained a reputation for treating cardiovascular and cancer. ❖ It is a first-line treatment for the fever and joint-pain symptoms of acute rheumatic fever and Kawasaki disease. ❖ Similarly, used as an intermediate and raw material in producing other medicines or chemical compounds like 4- hydroxycoumarin.  Synthetic Route of Paracetamol Reaction Mechanism Uses of Paracetamol ❖ Antipyretic drugs are used to reduce fever. Paracetamol is a safest antipyretic drug for children and pregnant women. ❖ An analgesic is a pain-reducing or relieving remedy. Paracetamol is an analgesic drug without any significant anti-inflammatory effects. ❖ It is available combined with other painkillers and anti-sickness medicines. ❖ It is also an ingredient in a wide range of cold and flu remedies. ❖ Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis. ❖ Paracetamol is readily absorbed from the gastrointestinal tract. 36  Dyes ❖ Dyes are colored organic compounds and they are used to impart the color to various substances/ materials like fabrics, paper, food, hair and drugs etc. ❖ Based on the solubility in water and/or an solvent, organic colorants fall into two classes, viz. dyes and pigments. 37  Preparation of Methyl Orange Azo Dyes  INDIGOTIN DYE ❖ Indigo dye is widely used to color blue jeans. ❖ The chemical in indigo which is responsible for the blue colour is indigotin, which is a dark blue powder at room temperature and is insoluble in water and ethanol. ❖ It is most soluble in chloroform, nitrobenzene and sulphuric acid. It has a fused nitrogen heterocyclic structure. ❖ To overcome the solubility problem, the dye is reduced to soluble leucoindigo (known as 'white indigo'), and applied to clothes in this form. When exposed to atmospheric oxygen it re-oxidises to the insoluble form and regains its colour.. ❖ Once the dye is applied to the fabrics, the dye will not be leached out even after several washings due to its insolubility in water. 39 Synthesis: 40