Substitution and Elimination Reactions of Alkyl Halides Essential Organic Chemistry Paula Yurkanis Bruice Chapter 9 Substitution and Elimination Reactions of Alkyl Halides

9.1 How Alkyl Halides React Figure: 10-00-02UN Title: Substitution versus Elimination Reaction Caption: In the substitution reaction the leaving group (usually an electronegative atom or electron-withdrawing group) is replaced by another atom or group. In the elimination reaction, the electronegative atom or electron-withdrawing group is removed along with an adjacent hydrogen atom to form a double bond. Notes: The atom or group that is being substituted or eliminated is called the leaving group.

Substitution Reactions One group takes the place of another. Y + R X R Y + X Y takes the place of X (Substitution) Y “displaces” X

Nucleophilic Substitution NUCLEOPHILIC DISPLACEMENT leaving group substrate - - N u : + R X R N u + :X nucleophile product The nucleophile “displaces” the leaving group. This is a “substitution” reaction: Nu substitutes for X (takes its place).

Example 1 iodide displaces bromide at carbon

DISPLACEMENT REACTIONS NUCLEOPHILIC SUBSTITUTION REACTIONS (substitution at carbon) can be compared to … ACID–BASE REACTIONS (substitution at hydrogen)

COMPARE THESE REACTIONS u : - + R X :X nucleophile substrate product leaving group DISPLACEMENT AT CARBON base acid conjugate :X - + B H X : DISPLACEMENT AT HYDROGEN

FIND WIDE APPLICATION SINCE WE CAN USE A WIDE RANGE OF NUCLEOPHILES THESE REACTIONS FIND WIDE APPLICATION SINCE WE CAN USE A WIDE RANGE OF NUCLEOPHILES

NUCLEOPHILES Nucleophile Product Class alkyl halides alcohols R'O- A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE THE SYNTHESIS OF MANY TYPES OF ORGANIC COMPOUNDS: R-Y + Nu R-Nu + Y Nucleophile Product Class R X alkyl halides alcohols R O H R'O- R O R' ethers R C N nitriles O esters R ' C O R R ' C C R alkynes R S H thiols

THE NUCLEOPHILE DOES NOT NEED TO BE CHARGED HOWEVER, REACTIVE ATOMS BEAR A LONE PAIR + - H O + R B r H O R + B r H H O H Under some circumstances water will react. H + - H O R + H O + B r 3 Nucleophile Product Class H O H R O H alcohols ' ethers R O H R' O R amines R N H N H 2 3 amines R ' N H R ' N H R 2

A Closer Look at Alkyl Halides Carbon and halogens have different electronegativity. Carbon-halogen bonds are polarized. Carbon is thought to be positive end of dipole. Nucleophiles can attack at positively charged carbon.

A Closer Look at the Reactions All substitution reactions follow a general scheme RBr + NaOH ROH + NaBr Two reactions follow ... From the outcome they look Identical; however, a closer inspection shows they are different!

TWO “LOOK-ALIKE” REACTIONS RBr + NaOH ROH + NaBr C H 3 B r + O - 20% water N a 80% ethanol 1) 55oC Speed of reaction depends on two concentrations rate = k2[RBr][NaOH] high conc. NaOH C H 3 O + B r 20% water - N a 80% ethanol 2) (+ some alkene by E1, E2) 55oC rate = k1[RBr] Speed of reaction independent of nucleophile concentration low conc. NaOH

Two Different Substitution Reactions We can distinguish two reactions based on their kinetics. First is SN2, depends on substrate AND nucleophile concentration. Second is SN1, depends only on substrate concentration.

9.2 The Mechanism of An SN2 Reaction Figure: 10-00-06 Title: Example and Mechanism of an SN2 Reaction Caption: An SN2 reaction is a bimolecular reaction. This reaction requires two molecules in the rate-determining step of the mechanism. As the nucleophile approaches, the leaving group is displaced all at the same time. Notes: This reaction results in the inversion of configuration if the leaving group is attached to an asymmetric carbon.

SN2 - C H B r + N a O H C H O H + B r rate = k2[RBr][NaOH] 80% ethanol - C H B r + N a O H C H O H + B r 3 3 20% water 55oC rate = k2[RBr][NaOH] - H O 80% ethanol - C H B r C H O H + B r 3 3 20% water Rate dependence of the reaction is interpreted in a way that we expect a bimolecular reaction with a concerted mechanism SN2 substitution nucleophilic bimolecular

SN2 Reaction Rate dependence is 2nd order Two molecules have to come together to form new bonds Bimolecular reaction

Mechanism ENERGY PROFILE E N R G Y

Mechanism ENERGY PROFILE E N R G Y

Mechanism ENERGY PROFILE E N R G Y

Mechanism ENERGY PROFILE E N R G Y

Mechanism ENERGY PROFILE E N R G Y

Mechanism ENERGY PROFILE E N R G Y

Mechanism ENERGY PROFILE E N R G Y

Stereochemistry Old bond is broken simultaneously with the new bond formed. Well-defined outcome Stereochemistry is inverted

Factors Affecting SN2 Steric effects Approaching the polarized carbon gets more and more difficult.

Energy Profile of SN2 SN2

Figure: 10-00-07UN.T1 Title: Table 10.1 - Relative Rates of SN2 Reactions Caption: The relative rates for several alkyl halides are given. The methyl bromide is the most reactive. Notes: The methyl halides are the fastest that can undergo an SN2 reaction, tertiary alkyl halides are too slow to measure.

9.3 Factors that Affect SN2 Reactions Leaving Group I– > Br– > Cl– > F– The lower the basicity, the better the leaving group. Nucleophile HO– > H2O; CH3O– > CH3OH The better the base, the better the nucleophile NH2– > HO– > F–

Figure: 10-03-03UN Title: Factors Affecting SN2 Reactions Caption: If an alkyl iodide reacts under the same conditions as any other alkyl halide (with the same alkyl group), it will react the fastest. Alkyl fluorides react the slowest. Notes: The weaker the basicity of a group the better is its leaving ability. The weaker the base the better the leaving group.

Figure: 10-03-13UN Title: Various Nucleophiles Used in SN2 Reactions Caption: Many different nucleophiles can react with alkyl halides in a variety of synthesis reactions. Notes: All the nucleophiles have lone pairs of electrons to donate in the reaction.

9.4 The Mechanism of An SN1 Reaction Figure: 10-00-06 Title: Example and Mechanism of an SN2 Reaction Caption: An SN2 reaction is a bimolecular reaction. This reaction requires two molecules in the rate-determining step of the mechanism. As the nucleophile approaches, the leaving group is displaced all at the same time. Notes: This reaction results in the inversion of configuration if the leaving group is attached to an asymmetric carbon.

SN1 SN1 rate = k1[RBr] Rate depends only on substrate concentration. H C H 3 3 80% ethanol - H C C B r + N a O H H C C O H + B r 3 3 20% water 55oC C H C H 3 3 rate = k1[RBr] Rate depends only on substrate concentration. Two independent steps that differ significantly in speed. Unimolecular SN1 substitution nucleophilic unimolecular

SN1 Assuming the formation of a carbocation intermediate 3 3 80% ethanol - H C C B r + N a O H H C C O H + B r 3 3 20% water C H C H 3 3 slow O H fast C H 3 H C C + - + B r 3 C H 3 Assuming the formation of a carbocation intermediate as the rate-determining step, explains speed of reaction

SN1 Reaction profile

SN1 Reaction profile Bond gets longer

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2 sp2-Hybridized intermediate formed

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2 sp2-Hybridized intermediate formed Nucleophile approaches Rehybridization sp3  sp2 takes place

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2 sp2-Hybridized intermediate formed Nucleophile approaches Rehybridization sp3  sp2 takes place

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2 sp2-Hybridized intermediate formed Nucleophile approaches Rehybridization sp3  sp2 takes place Bond forms

SN1 Reaction profile Bond gets longer and longer Rehybridization sp3  sp2 sp2-Hybridized intermediate formed Nucleophile approaches Rehybridization sp3  sp2 takes place Bond forms

SN1 Energy Profile of SN1 carbocation intermediate transition state 2 N E activation energy2 2 R G activation energy1 Y starting step 1 step 2 D H material product REACTION COORDINATE

Figure: 10-04UN Title: Reaction Coordinate Diagram for an SN1 Reaction Caption: Reaction coordinate diagram for an SN1 reaction. This illustrates that the rate-determining step is the first step, which is the formation of the carbocation. It has the highest activation energy. Notes: Note the formation of the carbocation intermediate.

Figure: 10-04-02UN Title: Mechanism for an SN1 Reaction Caption: The mechanism for an SN1 reaction illustrates the formation of equal amounts of two products due to the formation of a carbocation intermediate. The nucleophile can attack either from the front or the back of the carbocation since it is planar in nature. Notes: If the leaving group is attached to an asymmetric carbon, then one product will have retention of configuration and the other product has inversion of configuration. This results in a pair of enantiomers being formed.

SN1 Rate dependence is 1st order Rate depends only on formation of cation Unimolecular reaction The intermediate requires rehybridization sp3sp2

Stereochemistry First, old bond is broken. In a second step, we form new bond. We have a carbocation intermediate. This requires rehybridization sp3  sp2 Stereochemical information is lost. Racemate formed.

9.5 Factors that Affect SN1 Reactions Cation stability 3o alkyl halide > 2o alkyl halide > 1o alkyl halide. Leaving group The weaker the bond, the easier to break. RI > RBr > RCl > RF Nucleophile NO EFFECT.

Figure: 10-04-01UN Title: Relative Reactivities of Alkyl Halides in an SN1 Reaction Caption: The most reactive alkyl halide is a tertiary alkyl halide while the least reactive is the primary alkyl halide. The alkyl iodides are more reactive than the other alkyl halides since it is a better leaving group. Notes: The formation of a tertiary carbocation intermediate is the most stable.

Figure: 10-03-17UN.T2 Title: Table 10.2 - Relative Rates of SN1 Reactions Caption: In these reactions the solvent and nucleophile are water. As can be seen the tertiary alkyl bromide is more reactive than the secondary. The primary and methyl are approximately equal and are fairly unreactive in this type of reaction. Notes: The tertiary carbocation is more stable which is why its reaction is faster.

9.6 Comparing SN2 and SN1 Reactions

Figure: 10-04-07UN Title: Comparison of SN1 and SN2 Reactions of a Cyclic Compound Caption: Comparison of an SN1 and an SN2 reaction on the same cyclic compound. This illustrates the differences in the products that are formed in each reaction. Notes: The SN1 reaction results in two products whereas the SN2 reaction results in one with the opposite configuration.

9.7 Elimination Reactions of Alkyl Halides In an elimination reaction the starting material loses the elements of a small molecule such as HCl or HBr during the course of the reaction to form the product.

Example Alkyl halide + strong base and heat  LOSS OF HCl

Elimination In this case the nucleophile reacts as a base; we observe elimination reactions. A hydrogen is removed from a carbon atom. The halogen is removed from the adjacent carbon. Note that the elimination reaction is the reverse of an addition reaction.

E2 Reaction THE REACTION IS A b-ELIMINATION The b-hydrogen b-carbon. is attached to the b-carbon. a-carbon b-carbon The functional group is attached to the a-carbon. Since the b-hydrogen is lost this reaction is called a b-elimination.

Mechanism of E2 B: B H H C C C C C l C l THE BASE TAKES THE b-HYDROGEN .. .. : C l : .. Bond formation (p bond) and breaking bonds (C-H and C-X s bond) take place simultaneously

Figure: 10-04-10UN Title: E2 Reaction - Elimination Caption: This is an example of an E2 reaction. This reaction is bimolecular. The mechanism shows that this reaction occurs in one step with the base removing the proton from a carbon that is adjacent to the carbon bonded to the halogen. Notes: The electrons that were bonded to the hydrogen in the reactant form the new p bond in the product.

WHAT HAPPENS IF THERE IS MORE Regioselectivity WHAT HAPPENS IF THERE IS MORE THAN ONE b-HYDROGEN? b ’ b a

Regioselectivity b b’ Major product is the one with lowest energy Major product - b-H 2-butene 2-bromobutane 1-butene Minor product – b’-H Major product is the one with lowest energy

Regioselectivity b b’ b`` b’’ = b In some cases we have more than two b-hydrogens b b’ 1-methylcyclohexene Major product - b-H Minor product – b’-H C H 3 N a O C H 3 C l C H O H / D 3 methylenecyclohexane b`` b’’ = b 1-methylcyclohexene

Figure: 10-04-19UN Title: Elimination Reaction Caption: In the elimination reaction the hydrogen that is removed is from a  carbon. The  carbon is the carbon that is directly attached to the leaving group. The  carbon is the carbon adjacent to the  carbon. Notes: If the  carbons are identical there will be only one product.

Figure: 10-05x Title: Reaction Coordinate Diagram for an E2 Reaction Caption: Reaction coordinate diagram for the E2 reaction of 2-bromobutane and methoxide ion. Notes: The formation of 2-butene is more stable, as illustrated.

Figure: 10-05-01UN Title: Relative Reactivities of Alkyl Halides in an E2 Reaction Caption: In an E2 reaction the elimination from a tertiary alkyl halide will produce a more substituted alkene; therefore, it reacts the fastest in this type of reaction. Notes: The tertiary alkyl halide will produce an alkene with three alkyl substituents.

E1 ALKYL HALIDES + WEAK BASE (SOLVOLYSIS) The removal of a b-hydrogen becomes difficult without a strong base and a different mechanism (ionization) begins to take place … … if the substrate is capable.

The E1 Elimination Reaction (two steps) weak base carbocation B : H H slow :X C C C C + step one + X 3o > 2o > 1o also favored if a resonance- stabilized carbocation is formed unimolecular step two fast rate = k[RX] C C Works best in a polar solvent. IONS FORMED

Figure: 10-04-13UN Title: E1 Reaction - Elimination Caption: This an example of an E1 reaction along with its mechanism. This reaction is unimolecular and involves the formation of a carbocation intermediate in the rate-determining step. Notes: This is a two-step mechanism. The stability of the carbocation intermediate influences this reaction.

E1 ENERGY PROFILE two-step reaction carbocation intermediate TS1 E N R starting material step 1 step 2 DH slow product

Regioselectivity Major products in E1 eliminations are the alkenes that are thermodynamically most stable.

Figure: 10-04-20UN Title: Elimination Reaction Caption: In the case of 2-bromobutane the two  carbons are not identical so two products can be formed. The major product will be the one that forms the more stable alkene. Notes: Remember that the most stable alkene is generally the most substituted alkene.

Figure: 10-06 Title: Reaction Coordinate Diagram for an E1 Reaction Caption: Reaction coordinate diagram for the E1 reaction of 2-chloro-2-methylbutane. The major product is the more substituted alkene because its greater stability causes the transition state leading to its formation to be more stable. Notes: Note the formation of a carbocation intermediate. The activation energy for the formation of the carbocation is high and therefore this is the rate-determining step.

9.9 Competition Between SN2/E2 and SN1/E1 Consider “concentration” and “reactivity” SN2/E2 are favored by a high concentration of a good nucleophile/strong base. SN1/E1 are favored by a poor nucleophile/ weak base.

10.10 Competition Between Substitution and Elimination Figure: 10-06-16UN Title: SN2 and E2 Reaction Conditions Caption: SN2 and E2 reactions occur under similar conditions. Both use high concentrations of a good nucleophile or strong base. Notes: These two reactions compete with each other.

Figure: 10-06-17UN Title: Primary Alkyl Halide Under SN2/E2 Conditions Caption: A primary alkyl halide can undergo both a substitution or an elimination reaction when reacted with a good nucleophile such as the methoxide ion. The SN2 product is favored in the case of a primary alkyl halide. Notes: Primary alkyl halides undergo mainly substitution reactions.

Figure: 10-06T05 Title: Table 10.5 - Summary of Products Expected in Substitution and Elimination Reactions Caption: Comparison of the products that are expected in substitution and elimination reactions with primary, secondary, and tertiary alkyl halides. Notes: Primary alkyl halides react only under SN2/E2 conditions, whereas tertiary alkyl halides will only undergo elimination reactions under these same conditions.

Figure: 10-06T06 Title: Table 10.6 - Stereochemistry of Substitution and Elimination Reactions Caption: A summary of the products formed in the different substitution and elimination reactions. Notes: