Organic Reactions and their mechanism, Slides of Pharmaceutical Chemistry

Download Organic Reactions and their mechanism and more Slides Pharmaceutical Chemistry in PDF only on Docsity! Medicinal Chemistry-I Course: Pharm 333 Faria Tasneem Lecturer Department of Pharmacy University of Asia Pacific Organic Reactions and Mechanisms Bond Fission: Bond fission means separation of two atoms from each other in a covalently bonded molecule. Bond Fission Homolytic fission Heterolytic fission Each of the atoms acquire one of the bonded electrons One of the atoms acquire both of the bonded electrons, because A is more electronegative than B, which thereby acquires both the bonding electrons and becomes negatively charged. Light Energy Carbonium Ions: An organic ion containing a positively charged carbon atom is called a carbonium ion THE RELATIVE STABILITIES OF CARBOCATIONS Carbonium ion being deficient in electrons is very unstable. Electron releasing group such as alkyl group adjacent to the carbon atom makes the carbonium ion stable by partial neutralization of the positive charge on carbon. Alkyl groups, when compared to hydrogen atoms, are electron releasing thus the order of stability of carbocations parallel the number of attached alkyl / methyl groups. > The relative stabilities of carbocations is 3° > 2° > 1° > methyl Reactions of Carbonium ion Proton loss + Combination with nucleophile Addition to an alkene Abstraction of Hydride ion Carbanions: An organic ion with a pair of available electrons and a negative charge on the central carbon atom is called a carbanion (carb, from carbon + anion, negative charge) Reactions of Carbanion Addition reaction Substitution reaction Stability of Carbanions: Carbanions being rich in electrons is very unstable, so electron attracting/withdrawing group such as CN, NO2 group makes the carbanion more stable More stable On the other hand, electron releasing group such as alkyl group adjacent to the carbon atom makes the carbanion ion less stable by increasing the electron density on the negatively charged carbon. The relative stabilities of carbanion is Methyl > 1° > 2° > 3° > > > Electrophiles: An agent which can accept an electron pair in a reaction is called electrophile. Electrophiles are electron-deficient. The name electrophile means (electro = electrons and philic = loving) “electron-loving” and indicates that it attacks regions of high electron density (negative centre) of the substrate molecules. Electrophiles Positive electrophiles Neutral electrophiles They are deficient of two electrons and carry a positive charge Neutral molecules with electron deficient centre C+ H H H Br :: : + B F F F Al Cl Cl Cl Nucleophile: An agent which can donate an electron pair in a reaction is called nucleophile. Nucleophiles are electron rich. The name nucleophile means (nucleo = nucleus and philic = loving) “nucleus-loving”. Since the nucleus is electrically positive, the nucleophile will attack regions of low electron density (positive centre) of the substrate molecules Nucleophiles Negative Nucleophiles Neutral Nucleophiles C: H H H - An excess electron pair and carry a negative charge N: H H H Br :: : : Posses spare electron pair and no charge Electron Displacement Effects Inductive effect: The permanent effect whereby polarity is induced on the carbon atom and the substituent attached to it due to minor displacement of bonding electron pair caused by their different electronegativities, is known as inductive effect or simply as I-effect. Inductive effect (I effect) refers to polarity produced in a molecule as a result of higher electronegativity of one atom compared to other Inductive effect Positive Inductive Effect (+ I effect) Negative Inductive Effect (- I effect) The substituent bonded to carbon atom is electron attracting /withdrawing group, it develops negative charge and the inductive effect is called negative inductive effect (-I effect) The substituent bonded to carbon atom which loses electrons toward carbon atom (electron releasing group), it develops positive charge and the inductive effect is called positive inductive effect (+I effect) H C H H H Standard -I Effect +I Effect -I Effect group (electron attracting/withdrawing group): NO2 > F > COOH > Cl > Br > I > OH > C6H5 +I Effect group (electron releasing group): (CH3)3C- > (CH3)2CH- > CH3CH2 - > CH3- C--C---C---X γ---β---α -I Effect +I Effect Hyperconjugative effect: Hyperconjugation effect takes place through the interaction of σ electrons of C-H bond with π electrons of the double bond. Greater the number of C-H bonds at α position to the unsaturated system, greater would be the electron release towards the terminal C (* mark) creating high electron density. Types of Reactions • Addition reaction • Substitution reaction • Elimination reaction • Rearrangement reaction The mechanism of the above reaction involves the following steps: Step 1# Hydrogen bromide gives a proton (H’*) and a bromide i: ion (Br). H-Br »=——-—-+ H* + Br Electrophile Nucleophile 4 Step 2 # . 1 ‘The proton (electrophile) attacks the x bond of ethylene to, | sive a carbonium ion. 24 BLE scncfncetah tee ate mea Sh Se chiasctee Iie wwamsaemriaee Ethylene Carbonium ion This step can in also be written as: — CH3-"CH2 The mechanism of the chove reaction involves the following steps: Step 1# Hydrogen cyanide gives a proton (H*) anda cyanide ion (CN’). H-CN ———> H’ + CN: -Electrophile. Nucleophile Step 2# The cyanide ion (nucleophile) attacks: he positively charged Carbonyl carbon to give the correspending anion; a ‘Step 3 # product. Electrophilic Addition reactions in Conjugated Dienes Conjugated dienes are compounds having two double bonds joined by one σ bond. Conjugated dienes are also called 1,3-dienes. 1,3-Butadiene (CH2=CH-CH=CH2) is the simplest conjugated diene. •A conjugated diene is more stable than an isolated diene because a conjugated diene has overlapping p orbitals on four adjacent atoms. Thus, its π electrons are delocalized over four atoms. Electrophilic Addition: 1,2- Versus 1,4-Addition The π bonds in conjugated dienes undergo addition reactions that differ in two ways from the addition reactions of isolated double bonds. Electrophilic addition in conjugated dienes gives a mixture of products. Conjugated dienes undergo a unique addition reaction not seen in alkenes or isolated dienes. Electrophilic addition of one equivalent of HBr to an isolated diene yields one product and Markovnikov’s rule is followed. Electrophilic addition in conjugated dienes gives a mixture of products 1,2-addition product - addition at the 1- and 2-positions - direct addition 1,4-addition product - addition at the 1- and 4-positions - conjugate addition Kinetic Versus Thermodynamic Products The amount of 1,2- and 1,4-addition products formed in electrophilic addition reactions of conjugated dienes depends greatly on the reaction conditions. When a mixture containing predominantly the 1,2-product is heated, the 1,4-addition product becomes the major product at equilibrium Nucleophilic substitution is a fundamental class of substitution reaction in which an "electron rich" nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom attached to a group or atom called the leaving group. In nucleophilic substitution reactions, the C–X bond of the substrate undergoes heterolysis, and the lone-pair electrons of the nucleophile is used to form a new bond to the carbon atom. A nucleophile is an the electron rich species that will react with an electron poor species. A leaving group , LG, is an atom (or a group of atoms) that is displaced as stable species taking with it the bonding electrons. SN2 reaction: When the rate of a nucleophilic substitution reaction depends on both of the concentration of substrate and nucleophile is known as SN2 reaction. In SN2 reaction, a lone pair of electron from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step. Since two reacting species are involved, rate-determining step of the reaction, this leads to the name bimolecular nucleophilic substitution, or SN2. Kinetics: The rate of the reaction depends on the concentration of substrate and the concentration of nucleophile. Rate of reaction ∝ [Substrate] [Nucleophile]. Thus, the reaction is bimolecular i.e. two species are involved in the rate-determining step. Reaction order: The reaction is second order overall The SN2 reaction: Substitution, Nucleophilic, bimolecular STEREOCHEMISTRY OF SN2 REACTIONS In an SN2 reaction, the nucleophile attacks from the back side, that is, from the side directly opposite the leaving group and this attack causes a change in the configuration of the carbon atom so the configuration of the carbon atom becomes inverted which is known as Walden inversion because the first observation of such an inversion was made by the Latvian chemist Paul Walden in 1896. Inversion of configuration can be observed when hydroxide ion reacts with cis-1-chloro-3-methylcyclopentane in an SN2 reaction Inversion of configuration can be also observed when the SN2 reaction takes place at a stereocenter (with complete inversion of stereochemistry at the chiral carbon center) SN1 reaction: When the rate of a nucleophilic substitution reaction depends only the concentration of substrate molecule is known as SN1 reaction. In an SN1 reaction, there is loss of the leaving group generates an intermediate carbocation which is then undergoes a rapid reaction with the nucleophile. Kinetics: The rate of the reaction depends on the concentration of substrate but not the concentration of nucleophile. Rate of reaction ∝ [Substrate]. Thus, the reaction is uniimolecular i.e. one species is involved in the rate-determining step. Reaction order: The reaction is first order overall The SN1 reaction: Substitution, Nucleophilic, unimolecular SN1 reaction proceeds with racemization In SN1 reaction, racemization (a reaction that transforms an optically active compound into a racemic form) takes place whenever the reaction causes chiral molecules to be converted to an achiral intermediate. The SN1 reaction proceeds with racemization because the intermediate carbocation is achiral and attacked by the nucleophile can occur from either side. The carbocation has a trigonal planar structure and is achiral. (S)-3-bromo-3-methylhexane (optically active) (S)-3-methyl-3-hexanol (R)-3-methyl-3-hexanol (optically inactive, a racemic form) This side open to attack This side shielded from attack (retention)(inversion) FACTORS AFFECTING THE RATES OF SN1 AND SN2 REACTIONS • The structure of the substrate • The concentration and reactivity of the nucleophile • The effect of the solvent • The nature of the leaving group. The effect of the structure of the substrate on SN2 reactions: In an SN2 reaction, the nucleophile attacks from the back side, that is, from the side directly opposite the leaving group. Substituents on or near the reacting carbon have a dramatic inhibiting effect. Simple alkyl halides show the following general order of reactivity in SN2 reactions: methyl > 1° > 2° >> 3° (unreactive) because the central carbon atom surrounded by bulky groups will be sterically hindered for SN2 reactions. A steric effect is an effect on relative rates caused by the space-filling properties of those parts of a molecule attached at or near the reacting site. Steric hindrance: the spatial arrangement of the atoms or groups at or near the reacting site of a molecule hinders or retards a reaction. Although most molecules are reasonably flexible, very large and bulky groups Thus, the order of reactivity in SN2 reactions: methyl > 1° > 2° >> 3° (unreactive) and in SN1 reactions: 3° > 2° > 1° > methyl (unreactive) Effect of the nature and the concentration of the nucleophile SN1 reactions: Neither the concentration nor the structure of the nucleophile affects the rates of SN1 reactions since the nucleophile does not participate in the rate-determining step. SN2 reactions: The rates of SN2 reactions depend on both the concentration and the structure of the nucleophile. A stronger nucleophile attacks the substrate faster. A strong nucleophile as well as high concentration of the nucleophile always favor the SN2 reactions A negatively charged nucleophile is always a more reactive nucleophile than its conjugate acid. HO– is a better nucleophile than H2O; RO– is a better nucleophile than ROH. “Nucleophilicity” measures the affinity (or how rapidly) of a Lewis base for a carbon atom in the SN2 reaction (relative rates of the reaction). “Basicity”, as expressed by pKa, measures the affinity of a base for a proton (or the position of an acid-base equilibrium). SOLVENT EFFECTS ON SN2 REACTIONS Protic Solvents: The solvent molecule has a hydrogen atom attached to an atom of a strongly electronegative element e.g. hydroxylic solvents such as alcohols and water Molecules of protic solvents form hydrogen bonds with the nucleophiles and slows down the rate of SN2 reactions. Polar Aprotic Solvent: Aprotic solvents are those solvents whose molecules do not have a hydrogen atom attached to an atom of a strongly electronegative element. Polar aprotic solvents are especially useful in SN2 reactions because polar aprotic solvents do not solvate anions to any appreciable extent because they cannot form hydrogen bonds. The rates of SN2 reactions generally are vastly increased when they are carried out in polar aprotic solvents. THE NATURE OF THE LEAVING GROUP The best leaving groups are those that become the most stable ions after they depart. Most leaving groups leave as a negative ion and the best leaving groups are those ions that stabilize a negative charge most effectively. The leaving group begins to acquire a negative charge as the transition state 1s reached in either an SN1 or SN2 reaction SN1 Reaction 5 +e +s tt %, / - eat NUQ J Ne Li. (rate-limiting step) / Transition state SN2 Reaction If 5-4 f Nut > a Krk ee x” seansitln state Stabilization of the developing negative charge at the leaving group stabilizes the transition state-Cewerstsfree-enerey) lowers the free energy of activation and increases the rate of the reaction. The effect of the leaving group is the same in both SN1 and SN2: Elimination reactions: Two or four atoms or groups attached to the adjacent carbon atoms in the substrate molecule are eliminated to form a multiple bond. Elimination reactions are important as a method for the preparation of alkenes. The two most elimination reactions are: • Dehydration (-H2O) of alcohols, and • Dehydrohalogenation (-HX) of alkyl halides. Dehydrohalogenation involves the elimination of the halogen atom and of a hydrogen atom from a carbon adjacent to the one losing the halogen. The reagent required is a base, whose function is to abstract the hydrogen as a proton. Dehydrohalogenation is a β elimination or1,2-elimination reaction because the carbon holding the halogen is designated as α or 1-carbon and elimination involves the loss of β or 2-hydrogen from β or 2-carbon adjacent carbon holding the halogen. There are three fundamental events in these elimination reactions: • Removal of a proton • Formation of the CC π bond • Breaking of the bond to the leaving group + 12 How does such an elimination reaction generate a double bond? Regardless of the exact mechanisms, • Halogen leaves the molecule as halide ion and hence must take its electron pair along. • Hydrogen is abstracted by the base as a proton and hence leave its electron pair behind. • It is this electron pair that is available to form the second bond, the π bond between the carbon atoms. + Types of elimination reactions: • Bimolecular Elimination Reaction (E2) • Unimolecular Elimination Reaction (E1) Zaitsev's rule, Saytzeff's rule or Saytsev's rule named after Alexander Mikhailovich Zaitsev is a rule that states that if more than one alkene can be formed by an elimination reaction, the more stable alkene is the major product. When an alkylhalide has two or three β carbons, a mixture of isomers is possible and the more substituted alkene is the major product because the compound that has a more highly substituted C=C double bond is more stable due to the electron donating properties of the alkyl group. • The major product will be the most highly substituted alkene, the product with the fewest H substituents on the double bonded carbons Unimolecular Elimination Reaction (E1): E1 reaction proceeds by first order kinetics and involves of two steps: Step 1: Substrate undergoes heterolysis to form halide ion and carbocation Step 2: The carbocation rapidly loses the proton to the base and forms alkenes + E1 reactions accompained by rearrangement, where structure permits 2° carbocation Methyl shift 3° carbocation Major productMinor product Hofmann rearrangement • Hofmann rearrangement is the organic reaction of a primary amide to a primary amine with one fewer carbon atom. • Primary amide is transferred into an intermediate isocyanat in the presence of bromine with sodium hydroxide • The intermediate isocyanate is hydrolyzed to a primary amine giving off carbon dioxide. Br R CS ie oO o LL ek H —_ ore ] R rR isocyanabe carbamic acid ——* BNE, +CO,°+H a Beckmann Rearrangement • When ketoxime is treated with an acidic catalyst such as H2SO4, H3PO4, SOCl2, PCl5 etc., it is converted into a substituted amide. • The reaction mechanism of the Beckmann rearrangement is generally believed to consist of an alkyl migration with expulsion of the hydroxyl group to form a nitrilium ion followed by hydrolysis