Chapter 7 Substitution Reactions 7.1 Introduction to Substitution Reactions Substitution Reactions: two reactants exchange parts to give new products

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1 hapter 7 Substitution eactions 7.1 Introduction to Substitution eactions Substitution eactions: two reactants exchange parts to give new products A-B + -D A-D + B Br 3 2 Br + Elimination eaction: a single reactant is split into two (or more) products. pposite of an addition reaction (hapter 8) A-B A + B Br Na Na-Br 139 Nucleophilic Substituion A nucleophile may react with an alkyl halide or equivalent (electrophile) such that the nucleophile will displace the halide (leaving group) and give the substitution product. haracteristics of a good leaving group a. Good leaving groups tend to be electronegative, thereby withdrawing electron density from the LG bond making more electrophilic (δ + ). b. Leaving group depart with a pair of electrons and often with a negative charge. Good leaving groups can stabilize a negative charge, and are the conjugate bases of strong acid

2 Increasing reactivity in the nucleophilic substitution reactions LG: -, 2 N -, - F - l - Br - I - elative eactivity: pka: << ,000 30,000 > harged Leaving Groups: conversion of a poor leaving group into a good one + Nu _ + Nu + 2 pk a of 3 + = Alkyl alide Naming alogenated rganic ompounds - Use the systematic nomenclature of alkanes; treat the halogen as a substituent of the alkane. F - fluoro l - chloro Br - bromo I iodo Structure of Alkyl alides eactivity of alkyl halide is dictated by the substitution of the carbon bearing the halogen primary (1 ) : one alkyl substituent secondary (2 ) : two alkyl substituents tertiary (3 ) : three alkyl substituents X X 1 carbon X 2 carbon X 3 carbon

3 7.3 Possible Mechanisms for Substitution eactions oncerted bond making and bond breaking processes occur in the same mechanistic step with no intermediate. Stepwise (non-concerted) reaction goes through distinct steps with a discrete reaction intermediate(s) The S N 2 Mechanism Kinetics Br rate = k [ 3 Br] [ - ] + [ 3 Br] = 3 Br concentration [ - ] = - concentration k = rate constant + Br Second-order reaction (bimolecular) the rate is dependent on the concentration of both reactants (nucleophile and electrophile) If [ - ] is doubled, then the reaction rate is doubled If [ 3 -Br] is doubled, then the reaction rate is doubled S N 2 Substitution, Nucleophilic, bimolecular (2 nd order)

4 Stereospecificity of S N 2 eactions the displacement of a leaving group in an S N 2 reaction has a defined stereochemistry (Walden Inversion). This results from backside attack by the nucleophile and inversion of configuration. (S)-(-) Malic acid [α] D = -2.3 Ag 2, 2 l (-)-2-hlorosuccinic acid Pl 5 Pl 5 l Ag 2, 2 (+)-2-hlorosuccinic acid ()-(+) Malic acid [α] D = +2.3 The rate of the S N 2 reaction is dependent upon the concentration of both reactants (nucleophile and electrophile) and is stereospecific; thus, a transition state for product formation involving both reactants (concerted reaction) explains these 145 observations. 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 leaving group are 180 from one another. The Nu bond is partially formed, while the X bond is partially broken (concerted). 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 (N ) approaches the alkyl halide carbon at an angle of 180 from the X bond. This is referred to as backside attack

5 Structure of the Substrate The degree of substitution (sterics) of the alkyl halide has a strong influence on the SN2 reaction. krel = > 1,000 krel = 1 krel = 100 krel = too slow to measure Steric crowding at the carbon that bears the leaving group slows the rate of the SN2 substitution. 147 Steric crowding at the carbon adjacent to the one that bears the leaving group can also slow the rate of the SN2 reaction Increasing reactivity in the SN2 reaction Br krel = < 3 2 Br 3 3 neopentyl isobutyl 2x < 3 2 Br 0.8 < 3 2 Br The SN1 Mechanism Kinetics: first order reaction (unimolecular) rate = k [-X] [-X]= alkyl halide conc. The nucleophile does not appear in the rate equation changing the nucleophile concentration does not affect the rate of the reaction. SN1 Substitution, Nucleophilic, unimolecular (1st order)

6 Must be a two-step reaction, with involvement of the nucleophile in the second step. The overall rate of a reaction is dependent upon the slowest step (rate-determining step) Step 1: Spontaneous dissociation of the 3 alkyl halide generates a carbocation intermediate. This is the rate-determining step. 3 δ δ LG Step 2: The carbocation reacts with the nucleophile. This step is fast. E a2 E a1 E a1 >> E a2 149 Structure of the Substrate Formation of the carbocation intermediate is rate-determining. Thus, carbocation stability greatly influences the reactivity. The order of reactivity of the alkyl halide in the S N 1 reaction parallels the carbocation stability. least stable << < < most stable least reactive X X X << << 3 < 1 halide 3 most reactive halide 3 halide K rel x 10 6 X

7 Primary (1 ) alkyl halides undergo nucleophilic substitution by an S N 2 mechanism only Secondary (2 ) alkyl halides can undergo nucleophilic substitution by either an S N 1 or S N 2 mechanism Tertiary (3 ) alkyl halides under go nucleophilic substitution by an S N 1 mechanism only Stereochemistry of S N 1 eactions 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). l arbocation is achiral Both enantiomers of the product are equally possible Summary of the S N 1 and S N 2 eactions

8 7.6 Drawing the omplete Mechanism of an S N 1 eaction Proton transfer at the beginning of an S N 1 processes arbocation rearrangements during an S N 1 processes 153 Summary of the S N 1 processes and its energy diagram

9 7.7 Drawing the omplete Mechanism of an S N 2 eaction Proton transfer at the beginning of an S N 2 processes + l l + 2 Proton transfer at the end of an S N 2 processes I + + I 155 Proton transfer before and after an S N 2 processes S Determining Which Mechanism Predominates Substrate (alkyl halide): sterics (S N 2) vs carbocation stability (S N 1) methyl and 1 alkyl halides favor S N 2 3 alkyl halides favor S N 1 2 alkyl halides can react by either S N 1 or S N 2 allylic and benzylic alkyl halides can react by either S N 1 or S N

10 The carbon bearing the halogen ( X) must be sp 3 hybridized - alkenyl (vinyl) and aryl halides do not undergo nucleophilc substitution reactions. 3 X + Nu: 2 1 X Nu X + Nu: X Nucleophile: Nucleophilicity is the term used to describe the reactivity of a nucleophile. The measure of nucleophilicity is imprecise. The S N 2 reaction favors better nucleophiles anionic nucleophiles neutral nucleophiles _ Nu: + -X Nu- + X: + Nu: + -X Nu- + X: _ Nucleophilicity usually increases going down a column of the periodic chart. (polarizability and solvation) Nu _ alides: I > Br > l > F S > 157 Anionic nucleophiles are usually more reactive than neutral nucleophiles (e.g., > ). owever, anionic nucleophiles are usually more basic, which can lead to an increasing of competing elimination reactions. Solvolysis: a nucleophilic substitution in which the nucleophile is the solvent (usually for S N 1 reactions). Leaving Group: Good leaving groups are favors for both S N 1 and S N 2 reactions. Good leaving groups are the conjugate bases of strong acids. The ability to stabilize neagative charge is often a factor is judging leaving groups. (Fig 7.27) Sulfonates (conjugate base of sulfonic acids) are excellent leaving groups

11 Fig 7.27, p Sulfonates (ester of a sulfonic acids) - onverts an alcohols (very bad leaving group) into an excellent one (sulfonate). p-toluenesulfonate ester (tosylate): converts an alcohol into a leaving group; abbreviated as Ts. l S + S 3 3 tosylate Nu: S 3 Nu S Tos-l pyridine Ts Tos Ts Tos - [α] D = [α] D = [α] D = Tos [α] D = -7.0 Ts Tos [α] D = Tos-l pyridine [α] D =

12 Solvent Effects: Polar or non-polar; protic or non-protic. In general, polar solvents increase the rate of the S N 1 reaction. Solvent polarity is measured by dielectric constant (ε) δ + δ δ _ δ _ δ + δ _ S N δ + δ + δ N water formic acid DMS DMF acetonitrile methanol acetic acid ε = non-polar solvents: cyclohexane ε = 2 diethyl ether ε = 4 l sp 3 tetrahedral δ + δ _ l Solvent stablization of the transition state δ _ δ _ + δ _ δ _ δ _ δ _ sp 2 trigonal planar δ _ δ δ δ + δ + δ _ l _ δ + Solvent stablization of the intermediates δ In general, polar aprotic solvents increase the rate of the S N 2 reaction. Aprotic solvents do not have an acidic proton Br + N N 3 + Br Solvent: 3 2 DMS DMF 3 N relative reactivity: 1 7 1,300 2,800 5,000 ε = Polar, aprotic solvents sequester cations, which can make the anion more nucleophilic Nu

13 Summary of the S N 1 and S N 2 eactions Selecting eagents to Accomplish Functional Group Transformation converting one functional group into another.... with water or hydroxide affords an... Na Br NaBr S N 2... with an alcohols or alkoxides affords an.... TF I S N NaI Na... with an carboxylic acids or carboxylate anions affords an Ts + Ts K S N 2 K +... with halide ions affords an.... K + I Ts I + Ts K + S N

14 ... with cyanide anion affords a.... N : Br N + KBr K... with azide anion affords alkyl azides N N N Na Br N NaBr S N 2... with an thiols or thiolate ions affords a.... S l S + Kl S Li + N hapter 8: Alkenes: Structure and Preparation via Elimination eactions 8.1 Introduction to Elimination eactions Nucleophiles are Lewis bases. They can also promote elimination reactions of alkyl halides rather than substitution. S N2 3 - Br 3 elimination Br Br 2 elimination S N