hapter 8: Nucleophilic Substitution 8.1: Functional Group Transformation By Nucleophilic Substitution Nu: = l,, I Nu - Nucleophiles are Lewis bases (electron-pair donor) Nucleophiles are often negatively charged (more reactive) and used as their Li, Na, or K salt Nucelophiles react with alkyl halide (electrophile) to give substitution products. The carbon bearing the halogen ( ) must be sp 3 hybridized - alkenyl (vinyl) and aryl halides do not undergo nucleophilc substitution reactions 3 Nu: 2 1 3 2 1 Nu Nu: Nu 182 eactions of an alkyl halide...... with an alkoxide affords an ether TF 3 3 2 I S N 2 3 2 3 NaI Na... with an carboxylate anion affords an ester 3 2 S N 2 2 3 K K... with cyanide anion affords nitriles N N N Na N 3 Na S N 2... with azide anion affords alkyl azides N : 3-2 - 2-2 3-2 - 2-2 N K K 183 1
8.2: elative eactivity of alide Leaving Groups Nu _ 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 pk a of -, the stronger the acid. 184 Increasing reactivity in the nucleophilic substitution reactions LG: -, 2 N -, - F - l - - I - elative eactivity: pka: <<1 1 200 10,000 30,000 >15 3.1-3.0-5.8-10.4 harged Leaving Groups: conversion of a poor leaving group to a good one Nu _ Nu 2 pk a of 3 = -1.7 185 2
8.3: The S N 2 Mechanism of Nucleophilic Substitution _ If [ - ] is doubled, then the reaction rate may be doubled If [ 3 -] is doubled, then the reaction rate may be doubled The rate is linearly dependent on the concentration of two reactants is called a second-order reaction (bimolecular) For the disappearance of reactants: rate = k [ 3 ] [ - ] [ 3 ] = 3 concentration [ - ] = - concentration k= constant (rate constant) _ 186 The displacement of a leaving group in an S N 2 reaction has a defined stereochemistry (Walden Inversion) (S)-(-) Malic acid [!] D = -2.3 Ag 2, 2 l (-)-2-hlorosuccinic acid Pl 5 Pl 5 l Ag 2, 2 ()-2-hlorosuccinic acid ()-() Malic acid [!] D = 2.3 The rate of the S N 2 reaction is dependent upon the concentration of reactants; thus, the transition state for product formation must involve both reactants and explain the stereospecificity. 187 3
The mechanism of the S N 2 reaction takes place in a single step 2. The transition state of the S N 2 reaction has a trigonal bipyramidal geometry; the Nu and leavng group are 180 from one another. The Nu- bond is ~ half formed, while the - bond is ~half broken. The remaining three group are coplanar. 3. The stereochemistry of the carbon is inverted in the product as the Nu- bond forms fully and the leaving group fully departs with its electron pair. 1. The nucleophile ( ) approaches the alkyl halide carbon at an angle of 180 from the bond. This is referred to as backside attack 188 8.4: Steric Effects and S N 2 eaction ates - The rate of the S N 2 reaction is governed by steric effects of the alkyl halide. Steric crowding at the carbon that bears the leaving group slows the rate of the S N 2 substitution. k rel = 221,000 k rel = 1 k rel = 1,350 k rel = too slow to measure 189 4
Steric crowding at the carbon adjacent to the one that bears the leaving group can also slows the rate of the S N 2 reaction Increasing reactivity in the S N 2 reaction 3 3 2 3 2 3 2 3 2 3 < 3 < < neopentyl k rel = 2 x 10-5 0.4 0.8 1 8.5: Nucleophiles and Nucleophilicity - Nucleophilicity is the Used to describe the reactivity of a nucleophile. The measure of nucleophilicity is imprecise. anionic nucleophiles neutral nucleophiles isobutyl _ Nu: - Nu- : Nu: - Nu- : _ Solvolysis: a nucleophilic substitution in which the nucleophile is the solvent. _ 190 Table 8.4: Nucleophilicity of common nucleophiles nucleophile relative rate I -, S -, S - >10 5 -, -, -, N -, N - 3 10 4 N 3, l -, F -, - 2 10 3 2, 1 2 10-2 Factors that control nucleophilicity: 1. Basicity - 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 4.7-1.7 191 5
Nucleophilicity usually increases going down a column of the periodic chart. Thus, sulfur nucleophiles are more reactive than oxygen nucleophiles. alides: I > > l > F. Negatively charged nucleophiles are usually more reactive than neutral nucleophiles. Note that elimination is a competing reaction with nucleophilic substitution; more basic nucleophile can promote elimination Factors that control nucleophilicity: 2. Solvation: small negative ions are highly solvated in protic solvents; large negative ions are less solvated and are more reactive.!! _!!! 192 8.6: The S N 1 Mechanism of Nucleophilic Substitution kinetics: first order reaction (unimolecular) rate = k [-] [-]= alkyl halide conc. The overall rate of a reaction is dependent upon the slowest step: rate-limiting step The nucleophile does not appear in the rate expression- changing the nucleophile concentration does not affect the rate of the reaction. Must be a two-step reaction. Unimolecular kinetic for nucleophilic substitution is observed for tertiary alkyl halides In general, the S N 1 reactions is not stereospecific - nucleophilic substitution of a chiral tertiary alkyl halide leads to a racemic product. 193 6
The Mechanism of the S N 1 eaction 1. Spontaneous dissociation of the 3 alkyl halide generates a carbocation intermediate. This is the rate-limiting step. 2. The carbocation reacts with the nucleophile, in this case the water solvent. This step is fast. The product is a protonated alcohol. E act 3. Loss of a proton from the protonated alcohol affords the 3 alcohol, which is the overall product of the reaction. E act (step 1) >> E act (step 2) 194 8.7: arbocation Stability and S N 1 eaction ates Formation of the carbocation intermediate is rate-limiting. Thus, carbocation stability greatly influences the reactivity. The order of reactivity of the alkyl halide in the S N 1 reaction exactly parallels the carbocation stability Tertiary (3 ) > K rel 2.5 x 10 6 1 Secondary (2 ) > Primary (1 ) > Methyl 8.8: Stereochemistry of S N 1 eactions - is actually a complicated issue. For the purpose of hem 220a, sect. 1 the stereochemistry of the S N 1 reaction results in racemization. A single enantiomer of a 3 alkyl halide will undergo S N 1 substitution to give a racemic product (both possible stereoisomers at the carbon that bore the halide of the reactant). 195 7
l 3 3 2 2 2 2 3 2 3 3 2 2 2 2 2 3 2 arbocation is achiral 3 3 2 3 2 3 2 2 2 3 2 2 2 3 Both stereoisomeric outcomes result 3 3 2 3 3 3 3 (3S,7S)-3-bromo-3,7-dimethyldecane (3S,7S)-3,7-dimethyldecan-3-ol (3,7S)-3,7-dimethyldecan-3-ol 8.9: arbocation earrangements in S N 1 eactions - Since carbocations are intermediates in S N 1 reactions, products resulting from carbocation rearrangements are possible 196 3 3 3 2,! 3 3 2 3 8.10: Effect of Solvent on the ate of Nucleophilic Substitution - In general, polar solvents increase the rate of the S N 1 reaction. Solvent polarity is measured by dielectric constant (ε) _! S!!!! 3 3 N 3 3 3! N 3 water formic acid DMS DMF acetonitrile methanol acetic acid ε = 80 58 47 38 37 33 6 3! non-polar solvent: hexanes 197 8
l sp 3 tetrahedral! l Solvent stablization of the transition state sp 2 trigonal planar!!! l _! Solvent stablization of the intermediates 198 In general, polar aprotic solvents increase the rate of the S N 2 reaction. Aprotic solvents do not have an acidic proton. 3 2 2 2 2 N 3 3 2 2 2 2 Solvent: 3 2 DMS DMF 3 N relative reativity: 1 7 1,300 2,800 5,000 8.11: Substitution and Elimination as ompeting eactions Nucleophiles are Lewis bases. They can also promote elimination reactions of alkyl halides rather than substitution _ 3 S N 2 3 2 1 alkyl halide _ 3 elimination 3 2 or 3 alkyl halide 199 9
Elimination is a competitive reaction with nucleophilic substitution. 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 3 200 Secondary halides: E2 is competitive with S N 2 and often gives a mixture of substitution and elimination products S N 2 is favored with nucleophiles that are weak bases - cyanide ion, azide ion, thiolate ion, halide ion 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 reactions does not occur with 3 halides 201 10
8.12: Nucleophilic Substitution of Alkyl Sulfonates Good leaving groups are the conjugate bases of strong acids Leaving group conjugate acid pk a F F 3.5 2 3-1.7 l l -7-9 I I -10 3 S 3 S -2.8 Sulfonates are excellent leaving groups. p-toluenesulfonate ester (tosylate): converts an alcohol into a leaving group; abbreviated as Ts or Tos 202 l S S 3 3 tosylate Nu: S 3 Nu 3 - S Tos-l pyridine Tos 3-3 Tos - [!] D = 33.0 [!] D = 31.1 [!] D = -7.06 - - Tos - 3-3 [!] D = -7.0 Tos [!] D = -31.0 Tos-l pyridine [!] D = -33.2 203 11
8.13: Looking Back: eactions of Alcohols with ydrogen alides 3 alcohols proceed by an S N 1 mechanism- racemization occurs through an achiral 3 carbocation 3 (S) S N 1 3 3 chiral but racemic achiral 2 alcohols proceed by both an S N 1 and S N 2 mechanismpartial scrambling of stereochemistry S N 1 ~ 26 % of the time achiral (S) S N 2 ~ 74 % of the time - () (S) (87 %) (13 %) (74 %) We will assume that 2 centers proceed by an S N 2 mechanism () () (13 %) (13 %) (S) 204 12