chapter 81 substitution reactions of alkyl halides: chapter 8

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Chapter 8 1 Substitution Reactions Substitution Reactions of Alkyl Halides: of Alkyl Halides: Chapter 8 Chapter 8

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Page 1: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 1

Substitution Reactions of Alkyl Substitution Reactions of Alkyl Halides:Halides:Chapter 8Chapter 8

Page 2: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 2

Contents of Chapter 8 Reactivity Considerations

The SN2 Reaction

Reversibility of the SN2 Reaction

The SN1 Reaction

Stereochemistry of SN2 and SN1 Reactions

Benzylic, Allylic, Vinylic & Aryl Halides

Competition between SN2 and SN1 Reactions

Role of the Solvent No Biological Methylating Reagents

Page 3: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 3

Substitution and Elimination A compound with an sp3 hybridized carbon

bonded to a halogen can undergo two types of reactions

Two different mechanisms for substitution are SN1 and SN2 mechanisms

These result in diff prods under diff conditions

Page 4: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 4

SN2 Mechanism

SN2 mechanism: C–X bond weakens as nucleophile approaches all in one step

Page 5: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 5

SN1 Mechanism

SN1 mechanism: C–X bond breaks first without any help from nucleophile

This is a two-step process

slow step

fast step

Page 6: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 6

Substitution Reactions

Both mechanisms are called nucleophilic substitutions

Which one takes place depends on the structure of the alkyl halide the reactivity and structure of the nucleophile the concentration of the nucleophile, and the solvent in which reaction is carried out

Page 7: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 7

The SN2 Reaction Bimolecular nucleophilic substitution

rate = k [alkyl halide][nucleophile]

Page 8: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 8

The SN2 Reaction

The inversion of configuration resembles the way an umbrella turns inside out in the wind

If a single chiral enantiomer reacts a single chiral product (inverted) results.

Page 9: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 9

Steric Accessibility in the SN2 Reaction

Page 10: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 10

The SN2 Reaction: Leaving Group Stability

Page 11: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 11

The SN2 Reaction: Nucleophile Basicity

stronger base weaker base better nucleophile poorer nucleophile

HO– > H2O

CH3O– > CH3OH

–NH2 > NH3

CH3CH2NH– > CH3CH2NH2

Page 12: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 12

The SN2 Reaction: Nucleophile Basicity

Comparing nucleophiles with attacking atoms of approximately the same size, the stronger base is also the stronger nucleophile

Page 13: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 13

The SN2 Reaction: Nucleophile SizeIn nonpolar solvents nucleophilicity order same as basicity order- size doesn’t matter

Page 14: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 14

The SN2 Reaction: Nucleophile SizeSize is related to polarizability

Page 15: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 15

The SN2 Reaction: Nucleophile Size and Type

Nucleophilicity ~ both size and basicity

Page 16: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 16

The SN2 Reaction: Nucleophile Bulkiness

Nucleophilicity is affected by steric effects A bulky nucleophile has difficulty getting near

the back side of a sp3 carbon

CH3CH2O CH3CO

CH3

CH3

ethoxide ion tert-butoxide ion

better nucleophile stronger base

Page 17: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 17

The SN1 Reaction

The more stable the C+ the lower the G‡, and the faster the rxn

Page 18: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 18

The SN1 Reaction

Page 19: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 19

The SN1 ReactionThe SN1 reaction leads to a mixture of stereoisomers

Page 20: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 20

The SN1 Reaction: Factors Affecting the Rate

increasing reactivity

RI > RBr > RCl > RF

Two factors affect the rate of formation of the carbocation ease with which the leaving group leaves

stability of the carbocation

increasing reactivity

3º alkyl halide > 2º alkyl halide > 1º alkyl halide

Page 21: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 21

The SN1 Reaction: Carbocation Rearrangements

Page 22: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 22

Stereochemistry of SN2 and SN1 Reactions

inversion

both enantiomers

Page 23: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 23

Competition Between SN2 and SN1 Reactions

Page 24: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 24

Competition Between SN2 and SN1 Reactions

TABLE 9.6 Summary of the Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions

methyl & 1o alkyl halides SN2 only

2o alkyl halides SN2 & SN1

3o alkyl halides SN1 only

benzylic & allylic halides SN2 & SN1 vinylic & aryl halides neither SN2 nor SN1

3o benzylic & allylic halides SN1 only

Page 25: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 25

Competition Between SN2 and SN1 ReactionsWhat are the factors that determine which What are the factors that determine which mechanism operates?mechanism operates? concentration of the nucleophileconcentration of the nucleophile reactivity of the nucleophilereactivity of the nucleophile solvent in which the reaction is carried outsolvent in which the reaction is carried out

For SN2 rate = k2 [alkyl halide][nucleophile]

For SN1 rate = k1 [alkyl halide]

Page 26: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 26

Competition Between SN2 and SN1 Reactions

An increase in the concentration of the nucleophile increases the rate of the SN2 reaction but has no effect on rate of SN1 reaction

An increase in the reactivity of nucleophile also speeds up an SN2 rxn but not an SN1 rxn

Page 27: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 27

Role of the Solvent The solvent in which a nucleophilic

substitution reaction is carried out has an influence on whether the reaction proceeds via an SN2 or an SN1 mechanism

Two important solvent aspects include solvent polarity whether it is protic or aprotic

Page 28: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 28

Solvent PolarityThe dielectric constant is a measure of how well the solvent can insulate opposite charges from each other

Page 29: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 29

Role of the Solvent Polar solvents have a high dielectric constant

Water Alcohols Dimethylsulfoxide (DMSO)

Solvents having O–H or N–H bonds are called protic solvents

Polar solvents without O-H or N-H bonds called polar aprotic solvents

Page 30: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 30

Role of the Solvent If charge on reactants(s) in slow step is

greater than the charge on the transition state, a polar solvent will slow down rxn (by stabilizing reactants)

If all reactant(s) involved in slow step are neutral polar solvent will speed up rxn

If reactant(s) involved in slow step are charged polar solvent slows down rxn

Page 31: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 31

SN1 Reaction: Effect of Solvent

Most SN1 reactions involve a neutral alkyl halide which needs to produce a C+

Consequently a polar solvent stabilizes the transition state more than the reactant

Increasing the polarity of the solvent speeds up such an SN1 reaction

Protic solvents stabilize the leaving group by H-bonding and thus stabilize the transition state

Page 32: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 32

SN2 Reaction: Effect of Solvent

Most SN2 reactions involve a neutral alkyl halide and a charged nucleophile

Consequently a polar solvent stabilizes the nucleophile more than the transition state and slows rxn

The nucleophiles used in SN2 reactions however are generally insoluble in nonpolar solvents - some solvent polarity is needed, but it’s best to use an aprotic solvent to avoid overstabilizing nucleophile reactant

Page 33: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 33

Competition Between SN2 and SN1 Reactions

When a halide can undergo both an SSNN2 2

and Sand SNN1 1 reaction:: SSNN2 will be favored by a high concentration 2 will be favored by a high concentration

of a good (negatively charged) nucleophileof a good (negatively charged) nucleophile SSNN2 will be favored in a polar aprotic solvent2 will be favored in a polar aprotic solvent

SSNN1 will be favored by a poor (neutral) 1 will be favored by a poor (neutral)

nucleophile in a polar protic solventnucleophile in a polar protic solvent

Page 34: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 34

Problem-solving Info Nucleophile strength

Protic solvent Size most important Look at basicity if same row of periodic table

Aprotic solvent- look at basicity only Strength in aprotic solvent > protic solvent First two points not strictly true but will work

in this course

Page 35: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 35

Problem-solving Info Electrophile strength

SN2 reactions Steric accessibility Electron withdrawing group (EWG) attached to C

reaction site Good leaving group

SN1 reactions Carbocation stability EWG not attached to reaction site Good leaving group

Page 36: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 36

Problem-solving Info Solvent polarity

Reduces rate with charged reactants Charge on both nucleophile and electrophile

important in SN2

Only electrophile important in SN1

Increases rate with uncharged reactants Reduces nucleophilicity Stabilizes leaving group for SN1

Page 37: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 37

Problem-solving Info Reaction speed comparisons

Increasing speed in SN1 reaction Polar solv/uncharged electrophile, vice-versa Relief of steric strain making C+ More stable carbocation formed Anything which destabilizes electrophile Increased leaving group stability (less basic)

Increasing speed in SN2 reaction Charge on electrophile & nuc vs. solv polarity

Page 38: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 38

Problem-solving Info Increased leaving group stability Less steric hindrance (both nuc & electrophile) Switch from protic to aprotic solvent Higher concentration of nucleophile More basic nucleophile Larger size of nucleophile’s attacking atom Anything which destabilizes nuc or electrophile

Stereochemistry SN1 reactions give both isomers at chiral C

SN2 reactions give only inversion at chiral C

Page 39: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 39

Problem-solving Info Carbocation rearrangements

Will occur if posible with SN1 Will not occur with SN2

SN1 vs SN2 chemistry Conditions which give SN1

Tertiary C reaction center C+ stability 2 & weak nuc (H-nuc pKa <7)

Carboxylates and sulfonates Neutral O nucleophiles Halides Neutral large-atom (row >2) nucleophiles

Page 40: Chapter 81 Substitution Reactions of Alkyl Halides: Chapter 8

Chapter 8 40

Problem-solving Info Conditions which give SN2

C+ stability index = 1 and unhindered rxn site C+ stability 2, not 3°, strong nucleophile

Any nuc with conj acid pKa 7 (Table 10.3 pg 373) Alkoxides and hydroxide Ammonia and amines Carbanions Sulfides Hydride Nitrogen anions

In this text “high conc” of nuc is code for SN2 Other conditions give SN1/SN2 mixture