Organic Intermediates and Reaction Transformations - Module 3 PDF

Module-3 Organic intermediates and reaction transformations Contents…. (6 h) intermediates - stability and structure of carbocations, carbanions Organic and radicals; (2 h) Aromatics (aromaticity) and heterocycles (3, 4, 5, 6 membered and fused systems); (2 h) Organic transformations for making...

Module-3 Organic intermediates and reaction transformations Contents…. (6 h) intermediates - stability and structure of carbocations, carbanions Organic and radicals; (2 h) Aromatics (aromaticity) and heterocycles (3, 4, 5, 6 membered and fused systems); (2 h) Organic transformations for making useful drugs for specific disease targets (two examples) and dyes. (2 h) 1  Organic Reaction ❖Most of the Intermediates organic reactions occur via a specific chemical species (intermediate) which is extremely reactive and short – lived (10-6 second to a few seconds). Isolation of such species seemed to have difficult task. ❖These reactive intermediates can have the valency of carbon atoms either 2 or 3. ❖ Examples of such reaction intermediates are carbocations, carbanions, free radicals, carbenes and nitrenes – and they are quickly converted into more stable molecules. ❖ However, fairly stable organic intermediates have been prepared such as carbenes and carbocations. ❖ Among all the intermediates, only carbanions have a complete octet around the carbon. 2 ❖ There are many other organic ions and radicals with charges and unpaired electrons  Carbocations Organic species having a positively charged carbon atom bearing only six bonded electrons are called carbocations. For example: 2 Structure: ❖ The carbon atom with a positive charge is referred as carbocation (or carbonium ion) 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 3 complete the octet of the electron-deficient carbon.  Classification of Carbocations Carbocations are classified as primary (1 ), secondary (2 ), and tertiary (3 ) on the basis of number of carbon atoms o o o (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 :: *Hyperconjugation means interaction of sigma bonds (C-H and C-C bonds) (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  Reactions of Carbocations  Carbocations are short lived and they react easily i. Lewis acid-base reaction  Lewis base will donate electron to carbocation  Reaction is very fast ii. Loss of a proton  Carbocations may lose a proton from the adjacent carbon  Presence of α hydrogens  Reactions of Carbocations ii Rearrangement reactions i.  Intramolecular migration of an alkyl/aryl/hydrogen  New positive charge generated at another carbon atom  Rearrangement is driven by carbocation stability 1,2-Hydride Methyl shift shift  Reactions of Carbocations iv. Addition to a double bond  Carbocation may add to a double bond  New positive charge generated at another carbon atom  New carbocation formed can add to another alkene 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 -CH 3 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". ❖ So, the carbocation II, although a 3° one, is less stable than the 3° carbocation I. ❖ 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  Carbanio ns The species containing negatively charged trivalent carbon atom is known as carbanion that has eight electrons. 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 sp 3 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. ❖ Among other intermediates, only carbanions have a complete octet around the carbon. 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 sp 2 hybridized (33.33% s character) carbon atom, which in turn is more stable than a carbanion at an sp 3 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: Predict the decreasing order of stability of the following simple carbanions. Because of the destabilizing influence of electron-donating effect of alkyl groups, the order of stability of these simple carbanions is as follows: 13  Reaction of Carbanions (i)Displacement Reaction Carbanion attacks an electropositive centre Attacks carbon atom having four bonds One group is displaced by incoming carbanion  Reaction of Carbanions (ii)Grignard Reaction  Grignard reagent is an organomagnesium compound (RMgX)  Carbanion of Grignard reagent attacks a carbonyl carbon  Product is a secondary or tertiary alcohol  Reaction of Carbanions (iii)Elimination Reaction  Carbanion intermediates are formed in E1cb reaction  Alpha carbon contains a leaving group  Formation of an alkene  Reaction of Carbanions (iv)Combination with a cation  Carbanion generated from nucleophile addition to alkene  Negative charge stabilized by combination with a cation  Cation can be a proton or any positive ion Question: Arrange the following carbanions in the 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 sp 3 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. 18  Free ❖ Homolytic cleavage of covalent Radicals 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 α-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, MeĊH 2 (with only three hyperconjugable α-H atom). The methyl radical, ĊH3 is least stable because the unpaired electron is not19at all (ii) Resonance: ❖ Resonance is a major factor influencing the stability of free radicals. ❖ When the carbon bearing the odd electron is α- 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. 20  Reactions of Carbon Radicals (i)Combination with other radicals  Carbon radicals either react to give termination products  Lead to formation of new radicals (propagation reaction)  Common example of termination reaction is recombination with other radicals.  Another termination product is from the disproportionation reaction  Reactions of Carbon Radicals (ii)Abstraction of H atom  Alkyl radicals tend to abstract a H atom  WhenH-atom leaves with one electron the other fragment is now left with an unpaired electron  Generates a new alkyl radical  Reactions of Carbon Radicals (iii)Addition to multiple bond  Radical formed may add to a double bond  This generates a new radical in the adjacent carbon  The newly generated radical can add to a nearby alkene molecule  Reactions of Carbon Radicals (iv)Decomposition of a radical  Radical formed may not be very stable  Radical can undergo further fragmentation  May liberate a neutral molecule and a new radical  Example: Decomposition of benzoxy radical  Reactions of Carbon Radicals (v)Rearrangement reactions  Less common than rearrangement of carbocations  Driven by radical stability  Example: Ring opening of cyclopropyl carbinyl radical  AROMATICITY Features of aromatic compounds Aromatic compounds are conjugated planar ring systems having delocalized pi- electron with alternating double and single bonds. ❖ They have high degree of stability due to filled bonding molecular orbital. ❖ The high degree of stability is associated with greater resonance energy. ❖ An aromatic compound with high potential energy is least stable. Resonance energy of some of the aromatic systems Ignition test for Aromatic Compounds: Place a small amount of compound on the end of a spatula or on a porcelain lid and apply the flame from a Bunsen burner. Aromatic compounds burn with a yellow 26 Exampl es: *Aromatic compounds have a diamagnetic, it means all electrons are in the bonding region and are paired in there energy levels 27 *Circulation of pi electrons called ring current in the presence of magnetic field  Features of non-aromatic compounds For a molecule to be non-aromatic it must be: Cyclic or acyclic Do not have a have a continuous and overlapping p-orbitals, i.e. on every atom in ring Non-planar May or maynot follow (4n+2)/4n pi electron system ❖ Huckel's rule applies to a compound only if there is a continuous ring of overlapping p orbitals, usually in a planar system. ❖ But, Cyclooctatetraene would be an non-aromatic compound because Huckel 's rule is not applied ❖ Cyclooctatetraene is more flexible than cyclobutadiene and it assumes a non-planar ‘tub 28 shaped’ conformation that avoids most of the overlap between pi bonds.  Features of anti-aromatic compounds For a molecule to be anti-aromatic it must: Be cyclic and planar Have a continuous, overlapping ring of p orbitals, i.e. on every atom in ring Delocalization of the π-electrons over the ring increases the electronic energy and decreases the stability. Posses 4n π-electrons ( 4, 8, 12, 16 ) as (n = 1, 2, 3 etc.) Tropylium ion Cyclic Planar Conjugate d Antiaroma tic ❖. Anti-aromatic systems exhibit a paramagnetic ring current (means unpaired electrons in the bonding regions in there energy levels there circulation of pi electrons), which causes protons on the outside of the ring to be shifted upfield while any inner protons are shifted downfield (eg-12-annulene), in sharp contrast to a diamagnetic ring current, which causes shifts in the opposite directions. ❖ Compounds that sustain a paramagnetic ring current are called paratropic; and are prevalent in 4, 8, 12, 16, 20… 29  Types of aromatic compounds 2π- electron system. Exampl es: I.It follows (4n+2)π- electron system. II.If electrons are delocalized, then compound is aromatic. iii. If electrons are not delocalized, then compound is non-aromatic. Iv. Compound will never be anti-aromatic. 4π- electron system. I. Belongs to 4nπ- electron system doesn’t follow Huckel’s rule. II. If electron is delocalized then compound is Anti-aromatic. III. If electron does not delocalized then compound is never aromatic then compound is non- aromatic. Benzene di cation, 6C, 4 pi electrons 30 (A)6π- electron system I. Belongs to (4n+2)π- electron system. II. If electron is delocalized then compound is aromatic. III. If electron does not delocalized then compound must be non-aromatic. 8π- electron system I. Belongs to (4n)π- electron system. II. If electron is delocalized then compound must be Anti-aromatic. III. If electron does not delocalized then compound is non-aromatic. 31  Cyclopentadienyl anion Stability Order: Aromatic > Non-aromatic > Anti-aromatic. Energy Order: Anti-aromatic > Non-aromatic > Aromatic 32 Questions ? Aromatic, Center pi electron is not part of aromatic, so it obeys Huckel rule, have10 pi electrons 33 Characteristics of 3-Membered Ring Heterocyclic Compounds Anti-aromatic Cyclic, Conjugated sp2 hybridised carbons 4 π elections ( 4n rule) Non-aromatic Cyclic no conjugated sp2 hybridised 34  Characteristics of 4-Membered Ring Heterocyclic Compounds The Azete is an anti-aromatic. While counting the number of π-electrons, you count the electrons which are delocalized over the ring. Anti-aromatic In this case the nitrogen lone pair is localised and does Cyclic not participate in resonance. Conjugated sp2 The nitrogen lone pair is in an sp2 orbital (red) which is hybridised carbons orthogonal to the π system (blue): 4 π elections ( 4n So, the total number of π-electrons is only four: two rule) from each double bond. Non-aromatic Cyclic no conjugated sp2 hybridised 35 carbons  Five Membered Heterocycle: Pyrrole H NMR: 1 Aromatic: Thus, 6π electrons δ Sp2 hybridised and planar Lone pair tied up in aromatic ring Pyrrole is π-electron excessive Thus, Electrophilic Aromatic Substitution is Easy Nucleophilic Substitution is Difficult 36 The nitrogen lone pair electrons are not part of the aromatic system. Pyrrole is aromatic but when nitrogen atom of pyrrole is protonated, it becomes non- aromatic. 37  Six Membered Heterocycle: Pyridine Heterocycle: any cyclic compound that contains ring atom(s) other than carbon (N, O, S, P). Cyclic compounds that contain only carbon are called carbocycles. Pyridine replaces the CH of benzene by a N atom (and a pair of electrons) Pyridine: pi-electron structure Hybridization = sp2 with similar resonance stabilization energy resembles benzene (6 pi- Lone pair of electrons not involved in aromaticity electrons) Pyridinium ion: pKa = 5.5 H NMR: 1 Piperidine: pKa = 11.29 δ diethylamine : pKa = 10.28 Pyridine is a weak base. Pyridine is π-electron deficient. Electrophilic aromatic substitution is difficult. Nucleophilic aromatic substitution is easy. 38 Few representative drugs -Aspirin -Paracetamol 39  Synthetic Route of  In the year of 1897, Bayer laboratory gave acetyl salicylic acid the Aspirin 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.  Synthesis of aspirin is an esterification reaction of salicylic acid and acetic anhydride with an acid catalyst (sulfuric or phosphoric acid). Mechanism of Aspirin Uses of Aspirin/Acetylsalicylic acid-(C 9H8O4) Synthesis ❖ 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 Synthesis of Paracetamol (acetaminophen or para-hydroxyacetanilide) Paracetamol from p-aminophenol by actylating it with acetic anhydride in the presence of 3-4 drops of concentrated sulphuric acid as catalyst Mechanism of Paracetamol Synthesis ❖ 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's available combined with other painkillers and anti-sickness medicines. ❖ It's 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 (group of lipids made at sites of tissue damage). 41  Dyes- Classification of Dyes ❖Example for dyes: Methyl Orange, Indigotin 42  Dyes Classification of ❖ Dyes are colored Dyes organic compounds and they are used to impart the color to various Based on source Based on substances/ materials of materials chromophores like fabrics, paper, food, Natural dyes Azo hair and drugs etc. e.g. Turmeric ❖ Based on the solubility in Anthraquinone water and/or an solvent, Synthetic dyes Indigoid organic colorants fall into e.g. Alizarin Red two classes, viz. dyes Nitro and pigments. Triarylmethane 43  Azo Dyes  Azo dyes are characterized by presence in the molecule of one or more azo groups —N = N—, which form bridges between organic residues, of which at least one is usually an aromatic nucleus.  Many methods are available for preparing azo compounds, but manufacture of azo dyes is always based on the coupling of diazonium compounds with phenols, naphthols, arylamines, pyrazolones or other suitable components to give hydroxyazo or aminoazo compounds or their tautomeric equivalents.  In the resulting dyes the azo group is the chromophore and the hydroxyl or amino group is an auxochrome. Preparation of Methyl Orange Na+ The first step is to dissolove sulfanilic acid in basic solution Cl- Na+ Formation of diazotized sulfanilic acid Cl- Addition of N, N-dimethyl aniline Triphenylmethane Dyes Phthalein dyes 45  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. 46  Synthesis: Synthesis: Dissolve 1 g. of o-nitrobenzaldehyde in 3 ml of pure acetone, add about an equal volume of water, which leaves a clear solution, and then, drop by drop, sodium hydroxide solution. Heat is developed and the solution becomes dark brown. After a short time the dye separates in crystalline flakes. Collect the precipitate at the pump after five minutes and wash, first with alcohol then with ether. Indigo so prepared is specially pure and has a beautiful violet lustre. Mechani sm 47