ELIMINATION REACTIONS : ELIMINATION REACTIONS Presented by
MPHARM I YR CONTENTS : CONTENTS Elimination reactions
Orientation of double bond
Conclusion Elimination reactions : Elimination reactions When two groups are lost from adjacent atoms, a new double bond is formed
Elimination reactions involve the loss of elements from the starting material to form a new bond in the product Beta elimination : Beta elimination Beta elimination in aqueous phase
Mechanism-E2, E2c, E1, E1cb,
Beta elimination in gaseous phase
Mechanism-Pyrrolytic elimination , free radical pathway Elimination reactions : Elimination reactions There are two types of beta elimination reactions
E2 Elimination reactions
E1 Elimination reactions
E1cb elimination Equations  and  illustrate examples of elimination reactions. In both reactions a base removes the elements of an acid, HX, from the organic starting material. : Equations  and  illustrate examples of elimination reactions. In both reactions a base removes the elements of an acid, HX, from the organic starting material. Elimination reactions : Elimination reactions The E2 and E1 mechanisms differ in the timing of bond cleavage and bond formation, analogous to the SN2 and SN1 mechanisms.
E2 and SN2 reactions have some features in common, as do E1 and SN1 reactions. E2 Elimination : E2 Elimination It is a bimolecular elimination reaction
This reaction is analogous to SN2 mechanism
Nucleophilic attack on proton in E2
Nucleophilic attack on carbon in substrate in SN2 E2 reactions : E2 reactions Mechanism
Orientation of elimination
Competing reactions Dehydrohalogenation : Dehydrohalogenation E2 Mechanism : E2 Mechanism E2 Mechanism : E2 Mechanism Two groups depart simultaneously with the proton being pulled off by a base.
This reaction is done in strong base at high concentration such as 1M NaOH in water E2 Kinetics : E2 Kinetics The increase in E2 reaction rate with increasing alkyl substitution can be rationalized in terms of transition state stability.In the transition state, the double bond is partially formed. Thus, increasing the stability of the double bond with alkyl substituents stabilizes the transition state (i.e., lowers Ea, which increases the rate of the reaction. : The increase in E2 reaction rate with increasing alkyl substitution can be rationalized in terms of transition state stability.In the transition state, the double bond is partially formed. Thus, increasing the stability of the double bond with alkyl substituents stabilizes the transition state (i.e., lowers Ea, which increases the rate of the reaction. E2 Elimination : E2 Elimination E2 Kinetics : E2 Kinetics It is a second order reaction
First order in relation to substrate
First order in relation to base
Rate = k[R-X]1[base]1 Effect of base on E2 elimination : Effect of base on E2 elimination There are close parallels between E2 and SN2 mechanisms in how the identity of the base, the leaving group and the solvent affect the rate.
The base appears in the rate equation, so the rate of the E2 reaction increases as the strength of the base increases.
E2 reactions are generally run with strong, negatively charged bases like¯OH and ¯OR. E2 Elimination : E2 Elimination E2C Mechanism : E2C Mechanism This takes place in weak bases as chloride in aprotic solvents
There is a spectrum of E2 transition state in which base can interact in transition with alpha carbon as well as beta hydrogen
Base interacts with alpha carbon E2c Mechanism : E2c Mechanism Characteristics of E2C elimination : Characteristics of E2C elimination They are favoured by good leaving groups
They are favoured by aprotic polar solvents
Reactivity is teritiary> Secondary> primary
Elimination is always anti
They follow Zaitsev’s rule. Stereochemistry of E2 elimination : Stereochemistry of E2 elimination E2 mechanism is stereospecific
The five atoms involved including the base should lie in one plane
There are two ways for elimination to happen Stereochemistry of E2 elimination : Stereochemistry of E2 elimination The H and X may lie trans to one another-180 degrees- anti peri planar
The H and X may lie cis to one another- 0 degrees dihedral angle- syn periplanar Anti Elimination and Syn elimination : Anti Elimination and Syn elimination Elimination from A conformation – anti elimination
Elimination from B conformation- syn elimination
Anti elimination is favoured over syn elimination in E2 elimination because of staggered conformation. Example of Anti elimination : Example of Anti elimination Syn-anti dichotomy : Syn-anti dichotomy It is a mechanism by which a trans olefin if formed by syn route and a cis olefin is formed by trans route
This type of elimination takes place in medium sized rings. Isotope effects : Isotope effects It is the change in the rate of reaction brought about by replacing a hydrogen atom by dueterium
C-D bond is usually stronger than C-H bond and is expressed as KH / KD Isotope effects : Isotope effects If the ratio is 7.00 , it means isotopically labelled bond is broken in rate determining step indication the reaction is E2 Orientation of double bond-The Zaitsev (Saytzeff) Rule : Orientation of double bond-The Zaitsev (Saytzeff) Rule when alkyl halides have two or more different carbons, more than one alkene product is formed.
When this happens, one of the products usually predominates.
The major product is the more stable product—the one with the more substituted double bond.
This phenomenon is called the Zaitsev rule. Slide 34: The Zaitsev rule: the major product in elimination has the more substituted double bond.
A reaction is regioselective when it yields predominantly or exclusively one constitutional isomer when more than one is possible. Thus, the E2 reaction is regioselective. E1 Mechanism : E1 Mechanism The E1 reaction proceeds via a two-step mechanism: the bond to the leaving group breaks first before the bond is formed. The slow step is unimolecular, involving only the alkyl halide. E1 and E2 Elimination : E1 and E2 Elimination The E1 and E2 mechanisms both involve the same number of bonds broken and formed. The only difference is timing.
In an E1, the leaving group comes off before the proton is removed, and the reaction occurs in two steps. In an E2 reaction, the leaving group comes off as the proton is removed, and the reaction occurs in one step. E1 Kinetics : E1 Kinetics An E1 reaction exhibits first-order kinetics
Rate=k[ R- X]1 E1 Kinetics : E1 Kinetics The rate of an E1 reaction increases as the number of R groups on the carbon with the leaving group increases : The rate of an E1 reaction increases as the number of R groups on the carbon with the leaving group increases E1 reactions are regioselective, favoring formation of the more substituted, more stable alkene. Zaitsev’s rule applies to E1 reactions also. : E1 reactions are regioselective, favoring formation of the more substituted, more stable alkene. Zaitsev’s rule applies to E1 reactions also. E1cb mechanism : E1cb mechanism In E1 mechanism , X leaves first and then H
In E2 mechanism two groups leave simultaneously
In E1cb, H leaves first and then X
This is a two step process called E1cb or carbanion mechanism, since the intermediate is a carbanion. E1cb- Carbanion mechanism : E1cb- Carbanion mechanism E1cb mechanism : E1cb mechanism E1cb mechanism is more likely found in elimination yielding triple bonds
It also takes place in substrate like Ph-CH2CH2Br since carbanion is stabilised by resonance with phenyl group
Found in substrates containing acidic hydogen and poor leaving groups eg ;ZCH2CH2OPh where Z is electron withdrawing group and OPh , a poor leaving group. Orientation of Elimination to form double bond : Orientation of Elimination to form double bond Bredt’s rule
Hoffmann’s rule Bredt’s rule : Bredt’s rule No matter what the mechanism is, a double bond does not go to a bridgehead carbon unless the ring size are large enough. Zaitsev’s rule : Zaitsev’s rule Zaitsev’s rule states that double bond goes mainly towards highly substituted carbon atom
In other words, in elimination reactions the hydrogen which is lost will come from most highly branched beta carbon. : For E1 elimination Zaitsev’s rule governs the orientation
For E2 elimination, the statement does not hold for it
In some cases the leaving group affect the direction of double bond ( E1cb mechanism)
Non Zaitsev product is more stable for steric reasons Limitations of Zaitsev rule Limitations of Zaitsev rule : Limitations of Zaitsev rule For anti E2 mechanism, trans beta hydrogen is available in one direction and double bond forms in that way
When trans beta hydrogen are available on 2 carbon atoms, two types of behaviour
i.e Zaitsev rule and Hoffmann rule. Hoffmann rule : Hoffmann rule Hoffmann rule states that the double bond formed during elimination goes mainly towards least highly substituted carbon atom
Elimination from compounds with charged nucleofuges eg: NR3+, SR2+ follow Hoffmann rule. Hoffmann rule : Hoffmann rule Hoffmann orientation is caused because the acidity of beta hydrogen is decreased by the presence of electron donating alkyl groups. Reactivity : Reactivity The effect of change brought by reactions in
Medium Effect of substrate : Effect of substrate Can stabilise and destabilise the following
Incipient double bond(between alpha & beta carbon)
Incipient positive charge on alpha carbon
Incipient negative charge affecting acidity of proton (beta groups)
They can exert steric effects. Effect of substrate : Effect of substrate Groups such as Ar and C=C increase the rate of mechanism whether they are alpha or beta
Electron withdrawing groups increase the acidity when they are in beta position but have little effect on alpha position unless they conjugate with double bond.
Br, Cl,NO2 ,CN in beta position increase the rate of E2 elimination Effect of E1 vs E2 vs E1cb( Substrate) : Effect of E1 vs E2 vs E1cb( Substrate) Alpha alkyl and aryl groups stabilise the carbocation character at transition state and shift the spectra towards E1.
Beta alkyl groups towards E1
Beta aryl groups towards E1cb
All electron withdrawing groups at beta position shift towards E1cb
Alpha alkyl groups with weak leaving groups ( E2c) Elimination Vs Substitution( Substrate) : Elimination Vs Substitution( Substrate) E2 predominates SN2 under second order conditions because alpha brancing presents steric hindrance for the base to attack the carbon
SN1 predominates E1 under first order conditions . Effect of Attacking base : Effect of Attacking base E1- external base is not required
Addition of external strong base shift towards E2.
Stronger bases and higher concentrations cause the mechanism to shift towards E1cb end of E1, E2, E1cb mechanism Effect of Attacking base : Effect of Attacking base Weak bases in aprotic solvents shift towards E2c reactions. Effect of Elimination over Substitution ( Attacking base) : Effect of Elimination over Substitution ( Attacking base) Strong bases favour elimination ( E2) over substitution (SN2) reactions in a non ionizing solvent
At very low baseor absence of base altogether in ionising solutions, SN1 predominates over E1. Effect of leaving group : Effect of leaving group Leaving groups in E2 elimination are charged nucleofuges (NR3, OHR+)- Hoffmann’s rule and (cl, Br, F)- Zaitsev’s rule
E1 elimination- OH2+,Cl, Br, I Effect of leaving group in E1, E2 and E1cb : Effect of leaving group in E1, E2 and E1cb Best leaving groups shift towards E2
Better leaving groups shift towards E1 ( because of ionisation with solvent)
Poor leaving groups shift towards E1cb end of spectrum( because electron withdrawing field effect increase the acidity of hydrogen) Effect of elimination over substitution (leaving group) : Effect of elimination over substitution (leaving group) E2 and SN2 reactions are not dependent on halide leaving groups, but there is a slight increase in elimination in the order of halide specified.
When OTs is leaving group, substitution predominates. Effect of medium : Effect of medium Effect of solvent on E1, E2 and E1cb
A polar environment enhance the mechanism that involves ionic intermediates
Neutral leaving groups follow E1 mechanismby increasing polarity and ionic strength
Polar aprotic solvents promote E2c mechanism Reference : Reference Advanced Organic Chemistry , Reactions mechanism and structure, J. March, John Wiley, pg : 1477 Thankyou : Thankyou