hapter 11: Nucleophilic Substitution and Elimination Walden Inversion (S)-(-) Malic acid [a] D = -2.3 Ag 2, 2 Pl 5 l Ag 2, 2 ()-2-hlorosuccinic acid l (-)-2-hlorosuccinic acid Pl 5 ()-() Malic acid [a] D = 2.3 The displacement of a leaving group in a nucleophilic substitution reaction has a defined stereochemistry Stereochemistry of nucleophilic substitution p-toluenesulfonate ester (tosylate): converts an alcohol into a leaving group; tosylate are excellent leaving groups. abbreviates as Tos Nu: = l,, I Nu - l S S 3 3 tosylate Nu: S 3 Nu - S 3 1
Tos-l pyridine Tos 3-3 Tos - [a] D = 33.0 [a] D = 31.1 [a] D = -7.06 - - Tos - 3-3 [a] D = -7.0 Tos [a] D = -31.0 Tos-l pyridine [a] D = -33.2 The nucleophilic substitution reaction inverts the Stereochemistry of the carbon (electrophile)- Walden inversion Kinetics of nucleophilic substitution eaction rate: how fast (or slow) reactants are converted into product (kinetics) eaction rates are dependent upon the concentration of the reactants. (reactions rely on molecular collisions) onsider: _ At a given temperature: If [ - ] is doubled, then the reaction rate may be doubled If [ 3 -] is doubled, then the reaction rate may be doubled A linear dependence of rate on the concentration of two reactants is called a second-order reaction (molecularity) _ 2
eaction rates (kinetic) can be expressed mathematically: reaction rate = disappearance of reactants (or appearance of products) For the disappearance of reactants: rate = k [ 3 ] [ - ] [ 3 ] = 3 concentration [ - ] = - concentration k= constant (rate constant) L mol sec For the reaction above, product formation involves a collision between both reactants, thus the rate of the reaction is dependent upon the concentration of both. Nucleophilic Substitution comes in two reaction types: S N 2 S N 1 S= substitution S= substitution N= nucleophilic N= nucleophilic 2= biomolecular 1= unimolecular rate = k [-] [Nu:] rate = k [-] 3
The SN2 eaction: Mechanism Steric effects in the SN2 reaction: For an SN2 reaction, the nucleophile approaches the electrophilic carbon at an angle of 180 from the leaving group (backside attack) the rate of the SN2 reaction decrease as the steric hindrance (substitution) of the electrophile increases. 4
Increasing reactivity in the S N 2 reaction 3 3 3 3 3 3 < 3 2 < 3 < < 3 realtive reactivity tertiary neopentyl secondary primary methyl << 1 1 500 40,000 2,000,000 Vinyl and aryl halides do not react in nucleophilc substitution reactions 3 Nu: 2 1 3 2 1 Nu Nu: Nu 3 ( 3 ) 2 uli 2 1 3 3 From hapter 10: NT a nucleophilc 2 1 substitution reaction The nature of the nucleophile in the S N 2 eaction: The measure of nucleophilicity is imprecise. Anionic Neutral _ Nu: - Nu- : Nu: - Nu- : Nu 3 - Nu- 3 - Nu = 2 relative reactivity= 1 3-2 500 N 3 700 l - 1,000-16,000 3-25,000 I - 100,000 N - 125,000 S - 125,000 5
Nucleophiles are Lewis bases Nucleophilicity roughly parallels basicity when comparing nucleophiles that have the same attacking atom Nu: 3 - - 3 2-2 relative reactivity: 25,000 16,000 500 1 pka of the conj. acid: 15.5 15.7 4.7-1.7 Nucleophilicity usually increases going down a column of the periodic chart. Thus, sulfur nucleophiles are more reactive than oxygen nucleophiles. I - > - > l -. Negatively charges nucleophiles are usually more reactive than neutral nucleophiles. The role of the leaving group in S N 2 reactions: Nu _ Nu _ Nu _ The leaving group is usually displaced with a negative charge The best leaving groups are those with atoms or groups that can best stabilize a negative charge. Good leaving groups are the conjugate bases of strong acids - - the lower the pka of -, the stronger the acid. 6
Nu _ d- d- Nu Nu _ Increasing reactivity in the S N 2 reaction LG: -, 2 N -, - F - l - - I - Tos - elative eactivity: pka: <<1 1 200 10,000 30,000 60,000 >15 3.45-7.0-8.0 harged Leaving Groups: conversion of a poor leaving group to a good one Nu _ Nu 2 pka of 3 = -1.7 The role of the solvent in S N 2 reactions: Descriptor 1: polar: high dipole moment _ d d d d d S water alcohols DMS non-polar: low dipole moment (hexanes) Descriptor 2: protic: acidic hydrogens that can form hydrogen bonds (water, alcohols) aprotic: no acidic hydrogens [( 3 ) 2 N] 3 P _ hexamethylphosphoramide (MPA) _ S DMS 3 N acetonitrile 3 N 3 dimethylformamide (DMF) 7
Solvation: solvent molecules form shells around reactants and dramatically influence their reactivity. d d d _ d d _ d _ d d _ d _ Y d d d d d d d d d _ d _ Polar protic solvents stabilize the nucleophile, thereby lowering its energy. This will raise the activation energy of the reactions. S N 2 reactions are not favored by polar protic solvents. Polar aprotic solvents selectively solvate cations. This raises the energy of the anion (nucleophile), thus making it more reactive. S N 2 reactions are favored by polar aprotic solvents. 3 2 2 2 2 N 3-3 2 2 2 2 - Solvent: 3 2 DMS DMF 3 N MPA relative reativity: 1 7 1,300 2,800 5,000 200,000 DE DE 8
The S N 1 eaction: kinetics: first order reaction (unimolecular) rate = k [-] [-]= alkyl halide conc. The nucleophile does not appear in the rate expressionchanging the nucleophile concentration does not affect the rate of the reaction! Must be a two-step reaction The overall rate of a reaction is dependent upon the slowest step: rate-limiting step The Mechanism of the S N 1 eaction 9
DG step 2 step 1 DG ˇstep 1 >> DG step 2 DG ˇstep 1 is rate-limiting eactivity of the Alkyl alide in the S N 1 eaction: Formation of the carbocation intermediate is rate-limiting. Thus, carbocation stability greatly influence the reactivity. Methyl < Primary (1 ) < Allylic _~ Secondary (2 ) < Tertiary (3 ) Benzylic _~ Increasing carbocation stability The order of reactivity of the alkyl halide in the S N 1 reaction exactly parallels the carbocation stability 10
Allylic and benzylic carbocations are stablized by resonance Stereochemistry of the S N 1 eaction: it is actually a complicated issue. For the purpose of hem 220a, sect. 2 the stereochemistry of the S N 1 reaction gives racemization. A chiral alkyl halide will undergo S N 1 substitution to give a racemic product 2 l 3 3 2 2 2 2 3 2 3 3 2 2 2 2 3 2 arbocation is achiral 3 3 2 3 2 3 2 2 2 3 2 2 2 3 enantiomers: produced in equal amount 11
The role of the leaving group in S N 1 reactions: same as for the S N 2 reaction Tos - > I - > - > l - ~ _ 2 harged Leaving Groups: conversion of a poor leaving group to a good one - 2 Nu: Nu The role of the nucleophile in S N 1 reactions: None Involvement of the nucleophile in the S N 1 reaction is after the rate-limiting step. Thus, the nucleophile does not appear in the rate expression. The nature of the nucleophile plays no role in the rate of the S N 1 reaction. The role of the solvent in S N 1 reactions: polar solvents are fovored over non-polar for the S N 1 reaction protic solvents are favored over aprotic for the S N 1 reaction Solvent polarity is measured by dielectric constant (e) exane e = 1.9 ( 3 2 ) 2 4.3 MPA 30 DMF 38 DMS 48 3 2 24 3 34 2 80 nonpolar polar aprotic protic 12
3 3 l 3 3 l 3 3 Solvent: Ethanol 40% 2 80% 2 2 60% Ethanol 20% Ethanol el. reactivity: 1 100 14,000 100,000 Increasing reactivity in the S N 1 reaction l sp 3 tetrahedral d d _ l Solvent stablization of the transition state d _ d _ d _ d _ d _ d _ sp 2 trigonal planar d d d l _ d Solvent stablization of the intermediates Stabilization of the intermediate carbocation and the transition state by polar protic solvents in the S N 1 reaction 13
Elimination eactions: Nucleophiles are Lewis bases. In the reaction with alkyl halides, they can also promote elimination reactions rather than substitution. : _ S N 2 2 1 alkyl halide : _ elimination 2 alkyl halide Elimination is a competitive reaction with nucleophilic substitution. Zaitsev s ule: When more than one alkene product is possible from the base induced elimination of an alkyl halide, the most highly substituted (most stable) alkene is usually the major product. 3 2 3 3 3 2 - Na 3 2 3 3 3 2 3 3 2 2 81% 19% 3 2 3 3 2 - Na 3 2 3 3 2 3 2 3 3 2 2 70% 30% 14
The E2 Elimination: rate = k [-] [Base] The E2 elimination takes place in a single step with no intermediate Stereochemistry of the E2 Elimination: The being abstracted and the leaving group must be in the same plane Syn periplanar: the and are eclipsed dihedral angle = 0 Anti periplanar: the and are anti staggered dihedral angle = 180 Generally, the anti periplanar geometry is energetically preferred (staggered conformation vs eclipsed) 15
In the periplanar conformation, the orbitals are already aligned for p-bond formation The E2 elimination has a defined geometric (stereochemical) outcome: meso B: anti periplanar will be cis on the alkene will be cis on the alkene E favored syn periplanar will be cis on the alkene will be cis on the alkene Z Anti periplanar geometry is usually preferred for E2 elimination 16
E2 elimination with halocyclohexane reactants 17
The E1 Elimination: rate = k [-] No geometric requirements for E1 elimination. Usually follows Zaitsev s ule 18
S N 2 vs E2 For primary alkyl halides S N 2 is favored with most nucleophiles E2 is favored with bulky bases (t-butoxide) 3 3 _ 3 t-butoxide is too bulky to undergo S N 2 3 3 _ 3 S N 2 3 3 3 3 3 _ 3 E2 3 3 3 Secondary halides: E2 is competitive with S N 2 and often gives a mixture of substitution and elimination products Tertiary alides: E2 elimination occurs with strong bases such as -, -, 2 N - (strongly basic conditions) E1 elimination occurs with heat and weak bases such as 2 or. (neutral conditions) The E1 elimination product is often a minor product with the major product arising from S N 1 reaction. S N 2 reaction does not occur with 3 halides 19