Subject Chemistry Paper No and Title 1; Organic Chemistry-I (Nature of bonding and Stereochemistry Module No and 25; Regioselectivity Title Module Tag CHE_P1_M25 CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 2.1 Different Examples of Regioselective Reactions 2.1.1 Regioselectivity in Addition Reactions 2.1.2 Addition of HBr to Alkenes 2.1.3 Hydroboration Reaction and Addition of Hydrogen and Bromine to Alkenes 2.1.4 Baeyer Villiger Oxidation 2.1.5 Birch Reduction 2.1.6 Electrophilic Aromatic Substitution 2.1.7 Diels Alder Reaction 2.1.8 Friedal Crafts Reaction 2.1.9 Regioselectivity of Elimination 2.2 How to Determine the Regioselectivity? 3. Summary CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity 1. Learning Outcomes After studying this module, you shall be able to Know what is regioselectivity. Understand the basic difference between regioselectivity and chemoselectivity. Identify the regioselectivity in various reactions. Calculate the regioselectivity for a particular reaction. 2. Introduction 2. What is Regioselectivity? Regioselectivity is known as the preference chemical bond breaking or making in one direction of over all other possible directions. It is certainly applicable to positions which many reagents affect during the course of the reaction. An example to consider is which proton a strong base will abstract from an organic molecule, or where on a substituted benzene ring a further substituent will add. If there occurs a preponderance over which regioisomer will be formed, then that reaction can be termed as regioselective. A particular example is when 2-propenylbenzene (1) reacts with NBS, it gives bromonium ion and followed by aq. acetone gives halohydrin (2) major and (3) minor product (Fig. 1). CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Another example is a 1-methylcyclohexene (4) react with Br2 and formation of cyclic bromonium ion and followed by ring opening of bromonium ion by H2O to gives (1S,2S)-2- bromo-1-methylcyclohexanol (5) as the major product (Fig. 2). If there is a possibility of more than one reaction occurring between a set of reactants under the reaction conditions, which are same, giving products that are constitutional isomers and if one product is formed in greater amounts than the others, the reaction is therefore summed up to be as a regioselective reaction. 2.1 Different Examples of Regioselective Reactions 2.1.1 Regioselectivity in Addition Reaction On the previous modules on addition, we talked about the basic pattern followed in addition reactions [breaking of the C-C double bond, formation of two new bonds to adjacent carbons] and how this is the exact opposite pattern of elimination reactions we have discussed earlier. 2.1.2 Addition of HBr to Alkene: Addition of HBr to 1-methylcyclohexene (4) is a regioselective reaction because it favours formation of a bond between the alkenes tertiary carbon and the bromine atom instead of alkene’s secondary carbon. This regioselectivity happens to form the basis for Markovnikov’s rule. CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity The addition reaction favours the formation of a more stable intermediate and consequently the product also is formed from this more stable intermediate. Therefore, the major product of the addition of HBr (where Br is some atom more electronegative than H) to a 1- methylcyclohexene (4) has the hydrogen atom in the less substituted position and Br in the more substituted position (7). However, The less stable carbocation which is also less substituted will still be formed to some extent, and will proceed to form the minor product with the opposite attachment of Br (8) (Fig. 3). 2.1.3 Hydroboration reaction and Addition of Hydrogen and Bromine to Alkenes Hydroboration–oxidation is a reaction which follows an anti-Markovnikov rule, with the boron is attaching to the less-substituted carbon. The hydroxyl group is coming from the H2O2 and NaOH. The hydrogen and hydroxyl group are added in a syn addition leading to cis stereochemistry. In this reaction, it’s observed that the product (9) is formed in much higher yield than the product (10) (Fig. 4). CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Fig. 5: Regioselectivity of hydroboration reaction CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity The hydroboration of α-pinene also provides a fine example of steric hindrance control in a chemical reaction. Considering the case of lesser complex alkenes employed in earlier examples, the plane of the double bond was often a plane of symmetry, and addition reagents could approach with equal ease from either side. In this case, the face of the double bond is covered by one of the methyl groups bonded to C-6 (coloured blue in the figure) blocking any approach from that side. Thus, the reagents trying to add to this double bond must therefore approach from the side opposite this methyl. Not all addition reactions produce regioisomer. For example, “hydrogenation” treatment of alkenes with a metal catalyst (palladium over carbon or Pd/C) and hydrogen gas, gives the following product (as shown in the figure 6). Since we are forming C-H bonds on both sides of the alkene, it’s not possible to form regioisomers here because it will only give only one product that is 1-methylcyclohexane (11). CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Fig. 6.1: Mechanism of regioselective hydrogenation of alkenes CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Fig. 7.1: Mechanism of regioselective bromination of alkenes The same is the case for the addition of bromine (Br2) to alkenes. Since we are forming C-Br on both carbons, regioselectivity is not occur because it produce only single product 1,2- dibromo-1-methyl-cyclohexane (12) is formed. 2.1.4 Baeyer-Villiger Oxidation: The Baeyer-Villiger oxidation is known to oxidize ketones to esters by employing peroxy acids. This is a regioselective reaction. In the aforementioned case discussed, the R' group is presumed to have greater migratory aptitude and thus preferentially, only one product is formed. This reaction encompasses the oxidative cleavage of C-C bond. The aldehydes may yield carboxylic acids or formates. In the latter case, final product is alcohols due to hydrolysis of unstable formates in the reaction conditions. Cyclic ketones yield lactones (cyclic esters). The Baeyer-Villiger oxidation is an bicyclo[2.2.1]heptan-2-one (13) in presence of peracids gives a lactone (14) (Fig. 8). CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Mechanism of Baeyer-Villiger oxidation: The peroxy group, initially adds to the carbonyl carbon to give a Criegee like intermediate. Subsequently, one of the group bonded to carbonyl carbon migrates to the electron deficient oxygen atom in a rate determining, concerted step and it is the rate determining step. Fig. 8.1: Mechanism of Baeyer-Villiger oxidation The substituents which can stabilize the positive charge can migrate readily. The migratory ability of different substituents follows the following estimated order: 3o-alkyl > cyclohexyl > 2o- alkyl > benzyl > aryl > 1o - alkyl > methyl. The electron withdrawing groups (-I groups) on peroxy acids enhance the rate of the reaction. CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity 2.1.5 Birch Reduction In Birch reduction where the radical-anion is protonated initially defines the structure of the product. With an electron donor such as methoxy (MeO) (15), alkyl protonation has been thought by some investigators as being ortho (i.e. adjacent or 1,2) to the substituent. Other investigators have assumed the protonation is meta (1,3) (16) to the substituent. With electron withdrawing substituents such as carboxylic acid (17) protonation has been supposed to come at the site (ipso) of the substituent or para (1,4) (18) (Fig. 9). CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Fig. 9.1. Mechanism of Birch reduction 2.1.6 Electrophilic Aromatic Substitution: Aromatic electrophilic substitution of toluene (19) in the presence of nitrous acid with acetic anhydride to gives 1-methyl-4-nitrobenzene (in 34% yield) (20) and 1-methyl-2-nitrobenzene (in 63% yield) (21) (Fig. 10). Since the electron donating groups are ring activators they direct the incoming electrophiles to the o- or p- positions. This is a clear example of regioselectivity. CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Fig. 10.1. Mechanism of nitration of toluene 2.1.7 Diels-Alder Reaction In Diels-Alder reaction a diene (22) bearing an EDG at C1 has its largest HOMO coefficient at C4, while the dienophile (23) has the largest LUMO coefficient at C2. Pairing these two coefficients gives the "1-(2-methylcyclohex-3-enyl)ethanone " product (24) as a major and “1- (5-methylcyclohex-3-enyl)ethanone” product (25) as a minor (Fig. 11). CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module no. 25: Regioselectiveity Fig. 11.1. Mechanism showing regioselectivity of Diels Alder reaction 2.1.8 Friedel-Crafts Reaction: Friedel-Crafts reaction in (4,4-dimethylcyclohex-1-enyl)trimethylsilane (26) by using acetyl chloride with aluminium trichloride to gives 1-(4,4-dimethylcyclohex-1-enyl)ethanone (27) (Fig.