Alkyl halides are polarized in the C-X bond, making

carbon δ+ (electrophilic). A nucleophile can attack this

carbon, displacing a halide ion (substitution).

Alternatively, a base can attack an H one carbon away

from the C-X bond, forming a double bond and displacing

a halide ion (elimination).

This chapter will involve the specifics of these reactions,

and the two mechanisms that each reaction can

undergo.

Chapter 11: Reactions of alkyl halides: nucleophilic substitutions

and eliminations

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Walden discovered a series of reactions that could

interconvert (-)-malic acid and (+)-malic acid.

It was later confirmed that a certain type of nucleophilic

substitution reaction will cause the inversion

configuration at a chirality center.

Inversion of stereochemistry

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Let's investigate the kinetics of the reaction of hydroxide

with methyl bromide:

Doubling the concentration of OH- or doubling the

concentration of CH3Br will double the reaction rate.

The rate equation is Rate =

Since concentrations of both reactants influence the

rate, they must both be involved in the rate-determining

step. The nucleophile attacks and simultaneously the

leaving group leaves in a concerted reaction.

Substitution

Nucleophilic

2nd-order

11.2 The SN2 reaction

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Changing energy of the reactant vs the transition state

have different effects on the reaction's rate:

Because the nucleophile must approach from behind (the

leaving group takes up the other side) - configuration is

inverted when the electrophilic carbon is a chirality

center.

11.3 Characteristics of the SN2 reaction

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The substrate is the compound that contains the

electrophilic carbon and the leaving group.

Additional alkyl groups on the electrophilic carbon in

the substrate make it more difficult for the nucleophile

to approach (this is known as steric hindrance.)

(This is actually a transition state rate effect - a

crowded transition state is too high in energy)

Substrate effects

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The nucleophile is the substance with a pair of electrons

that attacks the electrophilic carbon.

Nucleophiles are usually negative (forming a neutral

product) but can be neutral (forming a positive product).

Strong bases are also strong nucleophiles (as long

as they're not too branched). RO-, RnN-, RnC-�

Weak bases can be strong nucleophiles if they're

polarizable (electron cloud is large and mobile).

RS-, Cl-, Br-, and I- are non-basic nucleophiles.

�

A concentrated (no resonance) anion will be a

stronger nucleophile than a neutral species.

�

Nucleophile strength can be estimated this way:

Strong nucleophiles are higher energy reactants - this

reduces activation energy and makes the reaction faster.

Nucleophile effects

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Neutral leaving groups make negative products.�

Positive leaving groups make neutral products.�

The leaving group is the group that was originally

attached to the electrophilic carbon, but is released as

the carbon is being attacked. The leaving group becomes

more negative.

A good leaving group can stabilize the negative charge.

(This reduces transition state energy).

Strong bases (OH-, OR-, NH2-) make bad leaving groups.

Make an alcohol into a tosylate to make it a better

leaving group.

Leaving group effects

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Protic solvents contain an -OH or -NH group. These

electropositive hydrogens will stabilize a nucleophile

through hydrogen-bonding.

This will lower reactant energy and slow reaction rate.

Polar aprotic solvents do not have H-bonding and will

therefore leave the nucleophile more available for

attack. Acetone, DMSO, DMF, CH3CN, and ethers are

common.

Solvent effects

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Summary of SN2 effects

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A different substitution mechanism happens when

there's a hindered substrate, a poor nucleophile, and a

protic solvent.

The mechanism now has two steps, and only the

substrate concentration determines the mechanism - not

the nucleophile!

It's Substitution Nucleophic 1st-order

Rate =

11.4 The SN1 reaction

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The carbocation intermediate is flat and can be attacked

from either side by the nucleophile.

The SN1 mechanism

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Stabilization of the carbocation intermediate is the most

important consideration for the SN1 reaction:

Allylic and benzylic carbocations have resonance

stabilization.

The nucleophile is not important. Acidic reactants even

work well!

11.5 Characteristics of the SN1 reaction

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Protic solvents are able to solvate and stabilize the

carbocation intermediate, making the reaction faster.

(This is the opposite of SN2 - protic solvents solvated the

nucleophile making it less reactive. The nucleophile is not

important in the SN1 reaction.)

Solvent effects

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For elimination, we need a base to attack a hydrogen "β"

(1 carbon away) to the electrophilic carbon.

Many compounds have different β hydrogens to choose

from. Zaitsev's rule states that the most stable, most

substituted alkene product will be favored.

11.7 Elimination reactions of alkyl halides: Zaitsev's rule

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The E2 reaction requires a very specific arrangement of

the atoms in order for the mechanism to be concerted.

11.8 The E2 reaction

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The σ bonds must be aligned anti-periplanar in order to

make a π bond.

Compare with the direction of attack of the nucleophile

in an SN2 reaction. Both nucleophile and base must come

from the opposite direction of the leaving group.

This has consequences for double-bond stereochemistry.

The anti-periplanar geometry

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The anti-periplanar geometry only exists in a cyclohexane

ring when a β H and the leaving group are trans and axial.

If a t-butyl group prevents the H and LG from being axial,

E2 elimination cannot occur.

11.9 The E2 reaction and cyclohexane conformation

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no strong base�

2o or 3o substrate�

protic solvent�

If there's:

… the leaving group will leave spontaneously to form a

carbocation. Solvent can remove a proton to make the

Zaitsef elimination product.

Because of the same carbocation intermediate, E1 and

SN1 happen together. It will be a mixture of substitution

and elimination products.

11.10 The E1 reaction

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Strong bases have a R3C:-, R2N-, or RO- (no resonance)

PLUS these weak bases : R3N, RS-, Cl-, Br-, I-,

Strong nucleophiles include the above,

Polar aprotic solvents do not have any H-bonding (no

OH, NH, or FH). Common solvents are acetone, DMF,

THF, ethers, DMSO, CH3CN. These activate Nuc:-

Polar protic solvents have an H-bond donor like ROH and

H2O. These stabilize charged species (Nuc:- or C+)

All of these reactions require a good leaving group: for

our purposes, Cl-, Br-, I-, OTs-, and H2O are common

(they are RCl, RBr, RI, ROTs, and ROH2+ in the substrate)

SN1/E1: 2o or 3o reactant, protic solvent (stabilizes C+

intermediate) and weak base, neutral, or acidic

conditions) - C+ resonance and rearrangement common.

SN2: 1o or 2o reactant (steric hindrance), strong nuc

that's a weak base (prevents elim), and polar aprotic

solvent (makes nuc more reactive)

E2: 1o, 2o, or 3o reactant, strong base, and ß hydrogen

anti to LG (geometry required for E2)

11.12 Summary of reactivity

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Synthesis practice

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