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CH221 CLASS 19CHAPTER 11: REACTIONS OF ALKYL HALIDES NUCLEOPHILIC

SUBSTITUTIONS AND ELIMINATIONS

Synopsis. Class 19 begins considering the substitution and elimination reactions

of alkyl halides by discussing the SN2 mechanism and the factors that influence it.At the end, there is a short discussion of substitution reactions in synthesis.

Introduction

Because of the electrophilic nature of the halogen-containing carbon atom andthe corresponding slightly acidic nature of the hydrogen atoms on the adjacent

carbon (the -hydrogens), the reactions of alkyl halides are dominated bynucleophilic substitution (SN) and elimination (E):

SN Nu:-

+ C X CNu + :X-

EC C

H

X

Nu:-

acting as aprotic base C C

Nu-H

:X-

[Nu:- may or may not be involved in the rate determining step]

Indeed, nucleophilic substitutions and eliminations are two of the most importantreaction types in organic chemistry, where X is not necessarily (though it isfrequently) halogen.It was discovered, by Paul Walden in the late 19 th century, that certain reactionsoccur with inversion of configuration at the reaction site. This is now called theWalden inversion. Some years later, Kenyon and Phillips demonstrated thatcertain substitution reactions occur with inversion of configuration, but it wasntuntil the 1930s that Hughes and Ingold showed that complete inversion ofconfiguration accompanies all bimolecular nucleophilic substitutions, which werenow called SN2 reactions. The work (described above) of all these pioneers waswith primary or secondary alkyl halides or their equivalents, such as tosylates

(see later).

The SN2 Reaction

Many primary and secondary alkyl halides react with strong nucleophiles (seelater) in substitution reactions that involve just one step, in which the new bond ismade and the old one is broken in a synchronous manner:

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CH3 Br CH3HOHO + :Br

SN2

+:..

..

..

..- -

The kinetic rate law for such a reaction is

Rate = k[CH3Br][OH-

]Or, more generally, rate = k[RX][Nu-]The term SN2 was first used by Hughes and Ingold: it stands for bimolecularnucleophilic substitution.The chief features of the SN2 reaction are summarized below for thedisplacement of bromide from 2-bromobutane by hydroxide to give 2-butanol.

C

HCH3

C2H5

BrHO

"backside attack"

(180o reaction line)

C

H CH3

C2H5incomingnucleophile

(S)-2-bromobutane

C

CH3H

HO

C2H5

inversion ofconfiguration

+ Br

(R)-2-butanol

tetrahedral

tetrahedral

5-co-ordinate trigonalbipyramidal transition state

HO Br- --

+

=/

Any factor that increases G

at a particular temperature will lead to a slowerSN2 reaction at that temperature. This includes factors that lower the reactantenergy (such as effective solvation of the nucleophilic reagent) and those thatincrease the transition state energy (such as steric hindrance or unfavorable

electronic interactions). In a similar way, any factor that decreases G

willresult in a faster SN2 reaction

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Characteristics of SN2 Reactions

As implied above, some SN2 reactions occur readily (i.e. they are fast), whereasothers occur only slowly, or not at all. It is now time to examine the factors thatinfluence the rates of SN2 reactions.

These factors are inherent in the nature of the substratestructure, the nucleophile, the leaving group and the solvent.

Influence of the Substrate: Electronic and Steric Effects

It has long been known that in the reaction

R-Br + Cl- R-Cl + Br-,

Methyl bromide reacts most readily, followed by bromoethane, 1-bromopropane

(and other primary halides) and then various simple secondary alkyl halides. Thefollowing is a reactivity sequence:

Substrate (CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br

3o hindered 1o 2o 1o methyl(neopentyl)

Rel. rate

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ClNu:-

high energy transition state

Similarly, the lack of SN2 reactivity at bridgehead carbon atoms can be explained

by a high-energy transition state, this time arising partly from steric hindranceand partly by the inability of the reaction carbon to invert its configuration,because of ring strain:

Cl

Nu:-

1-chloronorbornane

The above examples all illustrate ways in which certain structural features candestabilize the transition state, that is to say, increase its energy (with respect to

the reactant ground state energy), thereby increasing G, so that the rate of

reaction is decreased. Other structural aspects can stabilize the transition state,thereby making the SN2 reaction more favorable. This can occur particularlywhen there are favorable electronic interactions in the transition state, such aswhen there is an unsaturated group conjugated with the reaction site. Considerthe data below for the following reaction, in acetone:

R-Cl + I- R-I + Cl-

R CH3CH2 CH2=CH-CH2 PhCH2 PhCOCH2

Rel. rate 1 33 93 105

The transition state in the last case above is strongly stabilized by delocalization,

via p- orbital overlap:

Influence of the Nucleophile

Under a given set of conditions, different nucleophiles have different reactivities(nucleophilic strengths or nucleophilicities), resulting in different SN2 reaction

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rates. For example, examine the data for the following reaction in aqueousethanol:

CH3-Br + Nu- CH3-Nu + Br-

Nucleophile H2O CH3COO

-

Cl

-

Br

-

OH

-

I

-

CN

-

SH

-

Rel. rate 1 500 103 8x103 16x103 11x104 12.5x104

It is evident from the above data that the best nucleophiles are generally thosewith the following characteristics.

1. The presence of a negative charge: anions are the bestnucleophiles.

2. Basic strength. When comparing nucleophiles that havethe same reacting atom (e.g. oxygen), those that are thestronger bases are generally the better nucleophiles, e.g.OH- is better than CH3COO

-, which in turn, is better thanH2O.

3. Size: larger simple anions are better nucleophiles thansmaller ones, e.g. I- is better than Br- , which in turn, isbetter than Cl-. This is mainly because of higherpolarizability and lower solvation requirements of larger

anions.

Cl-

l-

small anion - high solvation large anion low solvation

Influence of the Leaving Group

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The better the leaving group, the faster the SN2 reaction. The best leaving groups(X) are those that are best able to stabilize a negative charge: those that are theweakest bases and, consequently, those that are derived from the strongestacids (HX). The following general scale of reactivities is applicable to most SN2reactions.

Leaving group X CN- OH- NH2- OR- F- Cl- Br- I- TosO-*

Rel. reactivity

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The rates of SN2 reactions are affected by the solvent in different ways,depending much upon the nature of the nucleophile and the leaving group, butwe will consider here only the displacement of one anionic group by another.Consider the data below for the reaction

CH3CH2CH2CH2-Br + N3-

CH3CH2CH2CH2N3 + Br-

Solvent CH3OH H2O DMSO DMF CH3CN HMPA

Rel. rate 1 7 1300 2800 5000 2x105

It can be seen from the data that polar protic solvents, like water and methanolare the poorest, whereas the best are that are called polar aprotic solvents(DMSO to HMPA, above). This is because polar protic solvents readily solvateanionic nucleophiles, thereby stabilizing them and lowering their ground state

energies, as shown below.

OR

H

O

R

H O

R

H

O R

H

Nu:-

Polar aprotic solvents, on the other hand, although they dissolve salts (fromwhence anionic nucleophiles are derived), they solvate cations only, leaving theanions almost free of solvation and hence with higher ground state energies:

Na+N3-(s) + nHMPA(l) Na+(HMPA)n (solv) + N3

-(l)

It can be seen overleaf that the structures of polar aprotic solvents can readilyinteract with cations, but not with anions.

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S

CH3 CH3

O

N

CH3 CH3

CO H

CCH3 N [(CH3)2N]3 P O

Dimethyl sulfoxideDMSO

DimethylformamideDMF

Acetonitrile HexamethylphosphoramideHMPA

.. .... ..

:

::....

E.g. Na+

S

CH3 CH3

O

S

CH3CH3

O

SCH3

CH3

O OCH3

CH3

S

DMSO can also be writtenS

CH3 CH3

O

..

: :..

+

-

Summary of SN2 Characteristics

Substrate. Branching raises the energy of the transition state, increases G

and decreases the rate of reaction. The best substrates are methyl and primaryalkyl.

Nucleophile. More reactive nucleophiles are less stable, have higher ground

state energies, thereby decreasing G

and increasing the reaction rate. Thebest nucleophiles are large basic anions.

Leaving group. Good leaving groups (more stable anions) lower the energy of the

transition state, decreasing G and increasing the reaction rate.

Solvent. Protic solvents solvate the nucleophile, lower its ground state energy,

which increases G

and decreases the rate of reaction. Polar aprotic solventsdo not solvate the nucleophilic anion, leaving it with a higher ground state

energy, decreasing G

and increasing the reaction rate.

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Nucleophilic Substitution Reactions and Synthesis

Nucleophilic substitutions are important reactions in organic chemistry theyoccupy prominent positions in many organic syntheses. Indeed, we have seen a

number of examples already, but it will be useful to examine the following twoexamples again.

Two useful ways of converting alcohols to alkyl bromides.

if R is secondary

orprimary

PBr3 HBr if R is tertiary

R Br

R OH2.

C C

A very useful way of extending carbon frameworks and still retaininga reactive functional group ( ) for further synthesis.

+ Li+Br-+ CH2

C3H7

BrLi+

-: C2H5C C

C3H7

CH2C2H5C C1.

lithio 1-butyne

These examples will now serve both to illustrate a problem associated with SNreactions, arising from competitive elimination (E) reactions and to introduce thedifference between SN2 and SN1 reactions. Accordingly, the same two examplesalso give a short preview of the topics of the final two classes, S N1 reactions andelimination reactions.In example 1, note that the alkyl halide used is primary: good yields ofsubstitution product are obtained in this case. However, if the halide is secondaryor tertiary, elimination competes successfully with substitution, especially as thisnucleophile is also a very strong base.E.g.

C4H9C C

C4H9C CH

C4H9C C CH(CH3)2

CH3 CH CH3

Br

:

-

Na++

SN2

E2

7%

93%

+ CH3CH CH2

In the second example, tertiary alcohols react rapidly with HBr because thesubstitution mechanism is not SN2 but SN1, which involves the generation of acarbocation intermediate 3o cations are more stable than 2o or 1o cations:

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(CH3)3C OH (CH3)3C OH2 (CH3)3C

(CH3)3C Br

2-Methyl-2-propanol

..

.. H Br++

+

H2O

Br-

2-bromo-2-methylpropane

SN1

On the other hand, 1o and 2o alcohols react readily with PBr3 because thisreagent converts the poor leaving group OH into a very good one:

C5H11CH2 OH C5H11CH2 O PBr 2

H

C5H11CH2

Br

+ PBr3

..

.. +

Br-

SN2

Class Questions

1. What product would you expect from an SN2 reaction of (R)-1- bromo-1-phenylethane with cyanide ion (-CN)?

CCH3

H

C6H5

Brinversion

NC +: :- NC C

CH3H

C6H5

+ Br-

(R)-1-bromo-1-phenylethane (S)-2-phenylpropanenitrile

2. Which substance of the following pairs is more reactive as a nucleophile?(a) (CH3)2N- or (CH3)2NH (b) (CH3)3B or (CH3)3N (c) H2O or H2S(a) (CH3)2N

- (b) (CH3)3N (c) H2S

3. Rank the following compounds in order of their expected reactivity towardthe SN2 reaction:

CH3Br, CH3OTos, (CH3)3CCl, (CH3)2CHClCH3OTos > CH3Br >(CH3)2CHCl > (CH3)3CCl