Subject Chemistry

Paper No and Title Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

Module No and Title Module-23, Elimination Reactions: E1 and E2 mechanisms- Part-II Module Tag CHE_P9_M23

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

TABLE OF CONTENTS

1. Learning Outcomes 2. Introduction

3. Regio-Chemical Aspects of E1 And E2 Eliminations: Orientation of the Double Bond

3.1 Regiochemistry of E1 elimination

3.2 Regiochemistry of E2 elimination

4. Stereochemical aspects of E1 and E2 Elimination Mechanisms 4.1 Stereochemistry of E1 elimination

4.2 Stereochemistry of E2 elimination

5. E2 elimination in cyclohexane rings 6. Summary

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

1. Learning Outcomes

After studying this module, you shall be able to

 Know what is meant by elimination reactions  Perceive factors favouring elimination over substitution  Learn about the types of elimination reactions  Differentiate between the E1 and E2 mechanism  Identify set of conditions responsible for E1 or E2 mechanism

2. Introduction

The E1 and E2 eliminations present a fair degree of regioselectivity and stereo-selectivity which are governed by their mechanistic aspects. Before proceeding to a detailed discussion on these aspects, let us recall the main features of E1 and E2 eliminations as shown in table-1.

E1 elimination E2 elimination Rate = k [substrate] Rate = k [substrate][Base]

unimolecular Bimolecular Leaving group first departs and Concerted process; both the groups carbocation is formed from which (proton and leaving group) are removal of H takes place eliminated simultaneously.

Preferred in 3o >2o >1o substrates No such preference

No strong base required Stronger and bulky base in high concentration is required Strongly dependent on leaving group. Hydroxyl can never be a leaving group Hydroxyl can be converted to a better for E2 elimination leaving group via protonation by use of an acid No stereochemical requirement The leaving group must be trans to the Hydrogen involved

3. Regio-Chemical Aspects of E1 And E2 Eliminations: Orientation of the Double Bond

During elimination reaction, a double bond is generated. So, one is concerned with the regiochemistry i.e., the production of structural isomers which have the double bond in different positions. Elimination reactions may be either regiospecific or regioselective. Regiospecific elimination reactions produce only one isomer of an alkene. Regioselective elimination reactions, on the other hand, produce several different isomers, but give one isomer in major quantity than the others. This, in turn, depends on whether the reaction prefers to eliminate only one particular β-hydrogen or a mixture of β-hydrogens.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

If an elimination reaction produces the more highly substituted alkene, the reaction is said to follow the Saytzeff rule. On the other hand, if the elimination reaction forms the less substituted alkene, the reaction is said to follow the Hofmann rule. A number of factors including the nature of substrate, the leaving group, reaction conditions etc. determine what rule a given reaction may follow.

3.1 Regiochemistry of E1 elimination

E1 eliminations are regioselective and generate the alkene that has the more substituents, as the major product. Thus, the E1 reactions follow Saytzeff rule. This is due to the fact that in E1 eliminations, leaving group departs to produce first a carbocation. Thus the direction of the double bond is determined almost entirely by the relative stabilities of the olefins produced via elimination. The major product is the alkene that has the more substituents, because this alkene is the more stable of the two possible products. For example, 2-bromo-3-methylbutane undergoes E1 elimination to yield two alkene products viz. 3-methyl-1-butene and 2-methyl-2-butene. The major product is 2-methyl-2-butene because there are three alkyl substituents attached to the carbon—carbon double bond.

‘More substituted alkene is more stable’ does not necessarily explain why it is the one that forms faster. For this, we need to have a look on the transition state leading to the two alkenes. In the carbocation there is hyperconjugation involving each β-hydrogen. Since the hyperconjugation structures possess some double-bond character, the interaction with hydrogen is greatest at more highly substituted carbons; that is, there will be greater weakening of C−H bonds and more double-bond character at more highly substituted carbon atoms. This structural effect in the carbocation intermediate governs the direction of elimination and leads to the preferential formation of the more highly substituted alkene. More stable transition state is lower in energy, and results in faster formation of more substituted alkene, i.e. it is the thermodynamic product.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

3.2 Regiochemistry of E2 elimination

Most of the E2 reactions, involving good leaving groups (halides, sulfonates etc.) also follow the Saytzeff rule, i.e. lead to a more substituted alkene. This can be attributed to a similar transition state as discussed in the case of E1 elimination. Hence, halides (Br, Cl, I) give more substituted alkene, but E2 elimination of alkyl fluorides results in the least substituted alkene. When a base begins to abstract a proton from an alkyl fluoride, the fluoride ion has less tendency to leave compared to other halide ions as it is a poor leaving group. Therefore negative charge develops on the carbon that is losing the proton, giving the transition state a carbanion character (rather than an alkene character as shown previously) which is stabilized by highly electron-withdrawing fluorine and fewer electron-donating alkyl substituents. This subsequently results in the formation of least-substituted alkene.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

Similarly, E2 reactions involving other poor leaving groups, particularly those with quaternary ammonium salts, are said to follow the Hofmann rule and give primarily the less-substituted alkene. Moreover, when the proton to be removed is in the sterically more hindered position or when the base used for E2 elimination is a bulky base, exceptions to the Saytzeff rule occur. These situations lead to a high proportion of the less substituted alkene (Hofmann orientation).

However, when formation of a double bond can lead to extended conjugation with already present functional groups (C=O or C=C) or aryl ring, then irrespective of the mechanism, the conjugated product only predominates.

Similarly, eliminations in bridged cyclic compounds follow the Bredt rule, i.e. irrespective of the mechanism, a double bond never goes to the bridgehead carbon in rings of smaller size. This is simply a consequence of the strain induced by a planar bridgehead carbon, and so having a double bond on a bridgehead would be too unstable.

4. Stereochemical aspects of E1 and E2 Elimination Mechanisms

The E1 reaction mechanism is a two-step process that, as with the SN1 mechanism, usually loses all the stereochemical information of the substrate as the reaction proceeds. On the other hand, the E2 mechanism is a concerted mechanism. A concerted reaction usually requires that the substrate have a specific conformation that allows the orbitals of the bonds being broken to overlap the bonds being formed. It is only when the orbitals overlap, the electrons flow smoothly

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

from the breaking bonds to the forming bonds and consequently the reaction takes place. These aspects of elimination reactions are discussed as follows:

4.1 Stereochemistry of E1 eliminations

Considering the geometrical isomerism of the E1 elimination product, usually the formation of E- alkene is favoured over the Z-alkene. This is due to the steric factors of the transition states leading to these possible geometries, favouring E-geometry because the substituents can get farther apart from each other. So, E-alkene forms faster.

4.2 Stereochemistry of E2 eliminations

As discussed before, E2 elimination requires a stricter stereo-chemical requirement to occur. The alkene is formed by overlap of the C–H σ-bond with the C–X σ* antibonding orbital (X=leaving group). The two orbitals must lie in the same plane for best overlap, and there are two possible conformations for this viz. Hydrogen and leaving-group are either syn-periplanar, or anti- periplanar.

Of these two conformations, the anti-coplanar conformation (staggered) is generally more stable. Thus, most E2 eliminations occur when the substrate is in the anti-coplanar conformation. This is also illustrated below:

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

Syn-elimination Anti-elimination

 Not so efficient overlap between σ C-H  Efficient overlap possible between σ C-H bonding and σ* C-LG anti-bonding orbital. bonding and σ* C-LG anti-bonding orbital.  Repulsion between the attacking electron- rich base and electron-rich halogen on the  No repulsion between the attacking same side of the molecule. electron-rich base and electron-rich halogen on the opposite sides of the

molecule. Thus, anti-elimination is faster.

However, when the substrate itself is quite rigid and only one proton is available for taking part in elimination as shown in the figure below for the two diastereomers of (1- bromopropane-1,2-diyl)dibenzene, the E2-elimination can be stereo-specific and the reaction outcome will depend upon which diastereomer has been used for the reaction. So, for case A), only the E-alkene results while for case B), the Z-alkene results, as shown below. But, the second reaction is about ten times slower than the first one because of greater steric interactions between the two -Phenyl rings, shown clearly in the Newmann projections.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

Although the anti-TS maximizes orbital overlap and avoids the eclipsing that is present in the syn-TS, the latter, does occur in substrates where structure of a molecule is itself rigid and as a consequence, the hydrogen and leaving group are held syn-coplanar in an eclipsed or nearly eclipsed conformation. It has been found that syn-E2-elimination is extensive for quaternary ammonium salts. For example, elimination from the N,N,N-trimethylnorbornylammonium ion is exclusively syn.

Further, it was observed that anti stereochemistry is normally preferred for reactions involving good leaving groups such as bromide and tosylate. With poorer leaving groups (e.g., fluoride, trimethylamine), syn elimination becomes important. The factors that determine the ratio of syn:anti elimination products are complex, but following three aspects are believed to have a say in the reaction outcome:

1. Presence of base as an ion-pair in the reaction medium. An ion-pair promotes syn- elimination of anionic leaving groups which in turn can be explained by a TS in which the anion functions as a base and the cation assists in the departure of the leaving group. So, a non-dissociating solvent like benzene may lead to predominant syn-elimination product. 2. Steric and conformational effects: As already stated, if steric and conformational requirements are such that anti-elimination is not favourable, then syn-elimination occurs. For acyclic systems, such as N-(ββ-disubstituted-ethyl)-N,N,N- trimethylammonium ions, the presence of bulky β-substituents such as aryl or branched alkyls lead to a prevalent syn-elimination product.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

3. Strong bases exhibit a higher proportion of syn elimination.

5. E2 elimination in cyclohexane rings

Since cyclic systems like cyclohexanes have more strict conformational requirements, hence a dedicated discussion on their elimination outcomes is inevitable. In a six membered ring, the two leaving groups must be trans-diaxial so as to assume the requisite anti-coplanar arrangement for the E2 elimination to occur. For example, cis-4-t-butylcyclohexyl bromide undergoes E2 elimination at a rate about 500 times greater than the trans isomer since only the cis isomer permits anti elimination from the favoured chair conformation.

Now, consider the case of trans-1-chloro-2-methycyclohexane. One may predict that it undergoes E2 elimination to yield 1-methylcyclohexene. However, in reality, its E2 elimination generates a double bond only between C-1 and C-6 leading to exclusively 3-methylcyclohexene. This can be explained on the basis of conformational analysis of the starting product which undergoes ring- flipping to get the desired anti-coplanarity requirement for E2-elimination. Of course, the rate of reaction is slow as an individual molecule spends only a small amount of time in the required conformation (which is less-stable) with the chlorine axial.

Similarly, in case of menthyl chloride, the stable conformation has all the substituents as equatorial. When it is treated with sodium ethoxide in ethanol, it undergoes a very slow E2-

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

elimination via its lesser stable conformation having the required anti-coplanar relationship between the two leaving groups, to produce 2-menthene as the exclusive product.

However, for neomenthyl chloride, as it already has the requisite di-axial H and Cl-atoms, hence, E2 elimination is about 40 times faster for neomenthyl chloride than menthyl chloride because there is less steric strain in the transition state for neomenthyl chloride. It therefore leads to two products in accordance with the Saytzeff rule, with the highly substituted alkene as the more prominent one.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II

6. Summary

 Most E1 and E2 elimination reactions follow the Saytzeff rule for forming a double bond. The most highly substituted alkene is generally the most stable product, so it is the major product. A reaction following the Saytzeff rule is a regioselective reaction.

 E2 reactions involving poor leaving groups, particularly those with quaternary ammonium salts, are said to follow the Hofmann rule and give primarily the less- substituted alkene.

 Eliminations in bicyclic compounds follow the Bredt rule, i.e. irrespective of the mechanism, a double bond never goes to the bridgehead carbon in rings of smaller size.

 For E1 elimination, usually the formation of E-alkene is favoured over the Z-alkene. This is due to the steric factors of the transition states leading to these possible geometries, favouring E-geometry because the substituents can get farther apart from each other.

 An E1 mechanism loses all the stereochemistry at the reaction site due to the formation of a symmetrical carbocation intermediate.

 An E2 mechanism requires that the leaving group and electrophile be in the same plane. The rate of reaction for the anti-coplanar conformation is generally much higher than for the syn-coplanar conformation.

 For E2 elimination, the ratio of syn:anti elimination products depend upon the nature of substrate (steric and conformational effects), base (stronger base and presence of base as ion-pair) and use of non-polar solvents.

 For cyclohexyl rings, the substrate must attain a particular conformation which can satisfy the requirement of anti-coplanarity between the two leaving groups for a successful E2 elimination.

CHEMISTRY PAPER No. 9 : Organic Chemistry-III (Reaction Mechanism-2) Module-23, Elimination Reactions: E1 and E2 mechanisms-Part-II