Essential Organic Chemistry Paula Yurkanis Bruice Chapter 9 Substitution and Elimination Reactions of Alkyl Halides
9.1 How Alkyl Halides React
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 substrate leaving group Nu: - + R X R Nu + :X - nucleophile product The nucleophile displaces the leaving group. This is a substitution reaction: Nu substitutes for X (takes its place).
Example 1 H 3 C CH 2 Br + NaI acetone H 3C CH 2 I + NaBr soluble insoluble 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 DISPLACEMENT AT CARBON Nu: - + R X R Nu + :X - nucleophile substrate product leaving group DISPLACEMENT AT HYDROGEN B: - + H X B H + :X - base acid conjugate acid conjugate base
THESE REACTIONS FIND WIDE APPLICATION SINCE WE CAN USE A WIDE RANGE OF NUCLEOPHILES
NUCLEOPHILES A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE THE SYNTHESIS OF MANY TYPES OF ORGANIC COMPOUNDS: R-Y + Nu Nucleophile R-Nu + Y Product Class Cl -,Br -,I - R X alkyl halides OH - R OH alcohols R'O - R O R' ethers C N - C N O R' C O - R O R' C O R nitriles esters R' C C: - R' C C R alkynes SH - R S H thiols
THE NUCLEOPHILE DOES NOT NEED TO BE CHARGED HOWEVER, REACTIVE ATOMS BEAR A LONE PAIR H O H Under some circumstances water will react. + R Br H O H O H R + R O H - + Br H + H 3 O + + Br - Nucleophile Product Class H O H R O R ' NH 3 O H R' O H R alcohols ethers R NH 2 amines R' NH 2 R' NH R amines
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. Cl Br l H H H H H H H H H
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 1) 80% ethanol CH 3 Br + NaOH CH 3 OH + Br - 20% water 55 o C 2) rate = k 2 [RBr][NaOH] high conc. NaOH Speed of reaction depends on two concentrations H 3 C CH 3 C Br CH 3 + rate = k 1 [RBr] NaOH 80% ethanol 20% water low conc. NaOH 55 o C H 3 C CH 3 C OH CH 3 + Br - (+ some alkene by E1, E2) Speed of reaction independent of nucleophile concentration
Two Different Substitution Reactions We can distinguish two reactions based on their kinetics. First is S N 2, depends on substrate AND nucleophile concentration. Second is S N 1, depends only on substrate concentration.
9.2 The Mechanism of An S N 2 Reaction
80% ethanol CH 3 Br + NaOH CH 3 OH + Br - 20% water 55 o C rate = k 2 [RBr][NaOH] H O - CH 3 Br 80% ethanol 20% water CH 3 OH + Br - Rate dependence of the reaction is interpreted in a way that we expect a bimolecular reaction with a concerted mechanism S N 2 substitution nucleophilic bimolecular
S N 2 Reaction Rate dependence is 2 nd order Two molecules have to come together to form new bonds Bimolecular reaction
Mechanism ENERGY PROFILE E N E R G Y HO - Br Br -
Mechanism ENERGY PROFILE E N E R G Y HO - HO - Br Br -
Mechanism ENERGY PROFILE E N E R G Y HO - HO - Br Br -
Mechanism ENERGY PROFILE E N E R G Y HO - HO - Br Br -
Mechanism ENERGY PROFILE E N E R G Y HO - HO Br Br -
Mechanism ENERGY PROFILE HO - HO Br -- Br - E N E R G Y
Mechanism ENERGY PROFILE HO - HO Br - Br - E N E R G Y
Stereochemistry Old bond is broken simultaneously with the new bond formed. Well-defined outcome Stereochemistry is inverted
Steric effects Factors Affecting S N 2 Approaching the polarized carbon gets more and more difficult.
S N 2 Energy Profile of S N 2
9.3 Factors that Affect S N 2 Reactions Leaving Group I > Br > Cl > F The lower the basicity, the better the leaving group. Nucleophile HO > H 2 O; CH 3 O > CH 3 OH The better the base, the better the nucleophile NH 2 > HO > F
9.4 The Mechanism of An S N 1 Reaction
S N 1 H 3 C CH 3 C Br + NaOH 80% ethanol 20% water 55 o C H 3 C CH 3 C OH + Br - CH 3 CH 3 rate = k 1 [RBr] Rate depends only on substrate concentration. Two independent steps that differ significantly in speed. Unimolecular S N 1 substitution nucleophilic unimolecular
S N 1 H 3 C CH 3 C Br + CH 3 CH 3 OH 80% ethanol NaOH H C + Br - 20% water 3 C CH 3 slow H 3 C O H CH 3 C+ + Br - CH 3 fast Assuming the formation of a carbocation intermediate as the rate-determining step, explains speed of reaction
S N 1 Reaction profile CH 3 Br - Br CH 3 CH 3 - OH
S N 1 Reaction profile CH 3 Br - Br CH 3 CH 3 - OH Bond gets longer
S N 1 Reaction profile CH 3 Br - Br CH 3 CH 3 - OH Bond gets longer and longer Rehybridization sp 3 sp 2
S N 1 Reaction profile Br - CH 3 CH 3 CH 3 - OH Bond gets longer and longer Rehybridization sp 3 sp 2
S N 1 Reaction profile Br - CH 3 CH 3 CH 3 Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed - OH
S N 1 Reaction profile Br - CH 3 CH 3 CH 3 - OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place
S N 1 Reaction profile Br - CH 3 CH 3 CH 3 OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place
S N 1 Reaction profile Br - CH 3 CH 3 CH 3 OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place Bond forms
S N 1 Reaction profile Br - CH 3 CH 3 CH 3 OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place Bond forms
Energy Profile of S N 1 E N E R G Y transition state activation energy 1 carbocation intermediate 1 2 S N 1 transition state 2 activation energy 2 starting material step 1 step 2 DH REACTION COORDINATE product
S N 1 Rate dependence is 1 st order Rate depends only on formation of cation Unimolecular reaction The intermediate requires rehybridization sp 3 sp 2
Stereochemistry First, old bond is broken. In a second step, we form new bond. We have a carbocation intermediate. This requires rehybridization sp 3 sp 2 Stereochemical information is lost. Racemate formed. Br HO - OH + OH
9.5 Factors that Affect S N 1 Reactions Cation stability 3 o alkyl halide > 2 o alkyl halide > 1 o alkyl halide. Leaving group The weaker the bond, the easier to break. RI > RBr > RCl > RF Nucleophile NO EFFECT.
9.6 Comparing S N 2 and S N 1 Reactions
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. C H C X -HX
Example Alkyl halide + strong base and heat LOSS OF HCl H 3 CH 2 CH 2 CH 2 C Cl NaOH D H 3 CH 2 CCH CH 2 H 3 CH 2 CH 2 CHCH 3 Cl NaOH D H 3 CCH CH 2 CH 3
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 is attached to the b-carbon. H C C a-carbon b-carbon Cl 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 THE BASE TAKES THE b-hydrogen B: H B H C C Cl :.. : C C.. : Cl.. : Bond formation (p bond) and breaking bonds (C-H and C-X s bond) take place simultaneously
Regioselectivity WHAT HAPPENS IF THERE IS MORE THAN ONE b-hydrogen? b b H H C C Br a C
Regioselectivity b b Major product - b-h H 3 C CH CH CH 3 H H H H 2-butene H C C C C H H H Br H H 3 C CH 2 CH CH 2 2-bromobutane 1-butene Major product is the one with lowest energy Minor product b -H
Regioselectivity In some cases we have more than two b-hydrogens b b CH 3 Cl NaOCH 3 CH 3 OH/ D b`` 1-methylcyclohexene Major product - b-h Minor product b -H methylenecyclohexane b = b 1-methylcyclohexene
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) H C unimolecular C X rate = k[rx] weak base slow step one B: H C step two C carbocation C + fast C + :X 3 o > 2 o > 1 o also favored if a resonancestabilized carbocation is formed Works best in a polar solvent. IONS FORMED
E N E R G Y ENERGY PROFILE two-step reaction TS 1 Ea 1 carbocation intermediate Ea 2 TS 2 E1 starting material step 1 step 2 slow DH product
Regioselectivity H 3 C CH 3 E1 H 3 C H 3 C CH 3 H 3 C Cl major CH 3 + CH 3 minor CH 2 Major products in E1 eliminations are the alkenes that are thermodynamically most stable.
9.9 Competition Between S N 2/E2 and S N 1/E1 Consider concentration and reactivity S N 2/E2 are favored by a high concentration of a good nucleophile/strong base. S N 1/E1 are favored by a poor nucleophile/ weak base.
9.10 Competition Between Substitution and Elimination