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Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Based on McMurrys Organic Chemistry, 7th edition

Alkyl Halides React with Nucleophiles and Bases

Alkyl halides are polarized at the carbon-halide bond,

making the carbon electrophilic Nucleophiles will replace the halide in C-X bonds of many alkyl halides(reaction as Lewis base) Nucleophiles that are Brnsted bases produce elimination

Why this Chapter?

Nucleophilic substitution, base induced

elimination are among most widely occurring and versatile reaction types in organic chemistry Reactions will be examined closely to see: - How they occur - What their characteristics are - How they can be used

11.1 The Discovery of Nucleophilic Substitution Reactions

In 1896, Walden showed that (-)-malic acid could be

converted to (+)-malic acid by a series of chemical steps with achiral reagents This established that optical rotation was directly related to chirality and that it changes with chemical alteration

Reaction of (-)-malic acid with PCl5 gives (+)chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic acid The reaction series starting with (+) malic acid gives (-) acid

Reactions of the Walden Inversion

Significance of the Walden Inversion

The reactions alter the array at the chirality center The reactions involve substitution at that center Therefore, nucleophilic substitution can invert the

configuration at a chirality center The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Waldens cycle

11.2 The SN2 Reaction

Reaction is with inversion at reacting center

Follows second order reaction kinetics

Ingold nomenclature to describe characteristic step:

S=substitution N (subscript) = nucleophilic 2 = both nucleophile and substrate in characteristic step (bimolecular)

The SN2 reaction (also known as

bimolecular nucleophilic substitution) is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable leaving group attached to it - 'X' frequently a halide atom.

Kinetics of Nucleophilic Substitution

Rate (V) is change in concentration with time Depends on concentration(s), temperature, inherent

nature of reaction (barrier on energy surface) A rate law describes relationship between the concentration of reactants and conversion to products A rate constant (k) is the proportionality factor between concentration and rate Example: for S converting to P V = d[S]/dt = k [S]

Reaction Kinetics
The study of rates of reactions is called kinetics Rates decrease as concentrations decrease but the

rate constant does not Rate units: [concentration]/time such as L/(mol x s) The rate law is a result of the mechanism The order of a reaction is sum of the exponents of the concentrations in the rate law the example is second order


SN2 Process
The reaction involves a transition state in which both reactants are



SN2 Transition State

The transition state of an SN2 reaction has a planar

arrangement of the carbon atom and the remaining three groups


11.3 Characteristics of the SN2 Reaction

Sensitive to steric effects
Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides)


Reactant and Transition State Energy Levels Affect Rate

Higher reactant energy level (red curve) = faster reaction (smaller G). Higher transition state energy level (red curve) = slower reaction (larger G).


Steric Effects on SN2 Reactions

The carbon atom in (a) bromomethane is readily accessible resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

Order of Reactivity in SN2

The more alkyl groups connected to the reacting

carbon, the slower the reaction


The Nucleophile
Neutral or negatively charged Lewis base

Reaction increases coordination at nucleophile

Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral See Table 11-1 for an illustrative list



Relative Reactivity of Nucleophiles

Depends on reaction and conditions

More basic nucleophiles react faster

Better nucleophiles are lower in a column of the

periodic table Anions are usually more reactive than neutrals



The Leaving Group

A good leaving group reduces the barrier to a

reaction Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge


Poor Leaving Groups

If a group is very basic or very small, it is prevents

Alkyl fluorides, alcohols, ethers, and amines do not

typically undergo SN2 reactions.


Solvents that can donate hydrogen bonds (-OH or

The Solvent

NH) slow SN2 reactions by associating with reactants Energy is required to break interactions between reactant and solvent Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction


Types of solvent
In chemistry a protic solvent is a solvent that has a

hydrogen atom bound to an oxygen (as in a hydroxyl group) or a nitrogen (as in an amine group). In general terms, any molecular solvent that contains dissociable H+ is called a protic solvent. The molecules of such solvents can donate an H+ (proton). Conversely, aprotic solvents cannot donate hydrogen.


Polar protic solvent

Polar protic solvents are solvents that share ion dissolving

power with aprotic solvents but have an acidic hydrogen. In general, these solvents have high dielectric constants and high polarity. Common characteristics of protic solvents : solvents display hydrogen bonding solvents have an acidic hydrogen (although they may be very weak acids) solvents are able to stabilize ions cations by unshared free electron pairs anions by hydrogen bonding Examples are water, methanol, ethanol, formic acid, hydrogen fluoride, and ammonia.


Polar aprotic solvent

Polar aprotic solvents are solvents that share ion

dissolving power with protic solvents but lack an acidic hydrogen. These solvents generally have intermediate dielectric constants and polarity. Common characteristics of aprotic solvents: solvents do not display hydrogen bonding solvents do not have an acidic hydrogen solvents are able to stabilize ions Examples are dimethyl sulfoxide, dimethylformamide, dioxane and hexamethylphosphorotriamide, tetrahydrofuran.

Polar protic solvents are favorable for SN1

reactions, while polar aprotic solvents are favorable for SN2 reactions.


The solvent affects the rate of reaction

because solvents may or may not surround a nucleophile, thus hindering or not hindering its approach to the carbon atom. Polar aprotic solvents, like tetrahydrofuran, are better solvents for this reaction than polar protic solvents because polar protic solvents will be solvated by the solvent hydrogen bonding to the nucleophile and thus hindering it from attacking the carbon with the leaving group.




11.4 The SN1 Reaction

Tertiary alkyl halides react rapidly in protic solvents

by a mechanism that involves departure of the leaving group prior to addition of the nucleophile Called an SN1 reaction occurs in three distinct steps while SN2 occurs with both events in same step


SN1 Energy Diagram

Rate-determining step is formation of carbocation


Rate-Limiting Step
The overall rate of a reaction is controlled by

the rate of the slowest step The rate depends on the concentration of the species and the rate constant of the step The highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier)


Mechanism of SN1 reaction



Stereochemistry of SN1 Reaction

The planar

intermediate leads to loss of chirality A free carbocation is achiral Product is racemic or has some inversion



SN1 in Reality
Carbocation is biased to react on side opposite

leaving group Suggests reaction occurs with carbocation loosely associated with leaving group during nucleophilic addition Alternative that SN2 is also occurring is unlikely


Effects of Ion Pair Formation

If leaving group

remains associated, then product has more inversion than retention Product is only partially racemic with more inversion than retention Associated carbocation and leaving group is an ion pair


11.5 Characteristics of the SN1 Reaction

Substrate Tertiary alkyl halide is most reactive by this mechanism Controlled by stability of carbocation Since the rate-limitings tep in a n SN1 reaction is the spontaneous, unimolecular dissociation of the substrate to yield a carbocation, the reaction is favored whenever a stabilized carbocation intermediate is formed. The more stable the carbocation intermediate, the faster the SN1 reaction.


An allyl group is a substituent with the

structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene (-CH2-), attached to a vinyl group (-CH=CH2).


Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by

delocalization of charge (resonance-stabilized) Primary allylic and benzylic are also more reactive in the SN2 mechanism allylic and benzylic catbocatious are unusually stable because the unpaired electron can be delocalized over an extended orbital system




Effect of Leaving Group on SN1

Critically dependent on leaving group

Reactivity: the larger halides ions are better leaving groups p-Toluensulfonate (TosO-) is excellent leaving group


Nucleophiles in SN1
Since nucleophilic addition occurs after

formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile


Solvent in SN1
Solvent effects in the SN1 reaction are due largely to

stabilization or destabilization of the transition state


Polar Solvents Promote Ionization

Polar, protic and unreactive Lewis base solvents

facilitate formation of R+ Solvent polarity is measured as dielectric polarization (P) Nonpolar solvents have low P Polar solvents have high P values


Solvent effect of SN1 rxn

Since the SN1 reaction involves formation of

an unstable carbocation intermediate in the rate-determining step, anything that can facilitate this will speed up the reaction. The normal solvents of choice are both polar (to stabilize ionic intermediates in general) and protic (to solvate the leaving group in particular). Typical polar protic solvents include water and alcohols, which will also act as nucleophiles.



11.6 Biological Substitution Reactions

SN1 and SN2 reactions are well known in

biological chemistry Unlike what happens in the laboratory, substrate in biological substitutions is often organodiphosphate rather than an alkyl halide


11.7 Elimination Reactions of Alkyl Halides: Zaitsevs Rule

Elimination is an alternative pathway to substitution

Opposite of addition
Generates an alkene Can compete with substitution and decrease yield,

especially for SN1 processes


Zaitsevs Rule for Elimination Reactions

In the elimination of HX from an alkyl halide, the more

highly substituted alkene product predominates


Mechanisms of Elimination Reactions

Ingold nomenclature: E elimination

E1: X- leaves first to generate a carbocation

a base abstracts a proton from the carbocation E2: Concerted transfer of a proton to a base and departure of leaving group


11.8 The E2 Reaction and the Deuterium Isotope Effect

A proton is

transferred to base as leaving group begins to depart Transition state combines leaving of X and transfer of H Product alkene forms stereospecifically


Geometry of Elimination E2
Antiperiplanar allows orbital overlap and minimizes

steric interactions


E2 Stereochemistry
Overlap of the developing orbital in the transition

state requires periplanar geometry, anti arrangement


Predicting Product
E2 is stereospecific Meso-1,2-dibromo-1,2-diphenylethane with base

gives cis 1,2-diphenyl RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl


11.9 The E2 Reaction and Cyclohexane Formation

Abstracted proton and leaving group should

align trans-diaxial to be anti periplanar (app) in approaching transition state Equatorial groups are not in proper alignment


11.10 The E1and E1cB Reactions

Competes with SN1 and E2 at 3 centers

V = k [RX], same as SN1


Comparing E1 and E2
Strong base is needed for E2 but not for E1

E2 is stereospecifc, E1 is not
E1 gives Zaitsev orientation


E1cB Reaction
Takes place through a carbanion



11.11 Biological Elimination Reactions

All three elimination reactions occur in

biological pathways E1cB very common Typical example occurs during biosynthesis of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioester


11.12 Summary of Reactivity: SN1, SN1, E1,E1cB, E2

Alkyl halides undergo different reactions in competition,

depending on the reacting molecule and the conditions Based on patterns, we can predict likely outcomes


How to know what mechanism a reaction follows?? SN1? SN2? E1? E2?