Phản ứng hóa học của ankyl halogenua: Phản ứng thế nucleophil và

tách loạiTS. Trần Thượng QuảngBộ Môn Hóa Hữu cơViện Kỹ Thuật Hóa họcHUST

2

Ankyl halogenua phản ứng với tác nhân nucleophil và bazơ

Liên kết C-X phân cực Tác nhân nucleophil sẽ thay thế nguyên

tử halogen trong liên kết C-X

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Ankyl halogenua phản ứng với tác nhân nucleophil và bazơ

Các nucleophil có tính bazơ mạnh theo Brønsted gây ra phản ứng tách loại

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Phản ứng thế vs. Phản ứng tách loại

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8.11The Nature of Substitution

Substitution requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule.

A nucleophile is a reactant that can be expected to participate as a Lewis base in a substitution reaction.

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Substitution Mechanisms

SN1Two steps with carbocation intermediateOccurs in 3°, allyl, benzyl

SN2Concerted mechanism - without intermediateOccurs in primary, secondary

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Kinetics of Nucleophilic Substitution Rate is the change in concentration with time Depends on concentration(s), temperature, inherent nature

of reaction (energy of activation) A rate law describes the relationship between the

concentration of reactants and the overall rate of the reaction

A rate constant (k) is the proportionality factor between concentration and rate

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Kinetics of Nucleophilic Substitution

Rate = d[CH3Br]/dt = k[CH3Br][OH-1]

This reaction is second order: two concentrations appear in the rate law

SN2: Substitution Nucleophilic 2nd order

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8.12 The SN2 Reaction

Reaction occurs with inversion at reacting center

Follows second order reaction kinetics Ingold nomenclature to describe rate-

determining step:S=substitutionN (subscript) = nucleophilic 2 = both nucleophile and substrate in rate-

determining step (bimolecular)

SN2 Process

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SN2 Transition State

The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups

Hybridization is sp2

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8.13 Characteristics of the SN2 Reaction Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Unhindered secondary halides react

under some conditions Tertiary are unreactive by this path No reaction at C=C (vinyl or aryl halides)

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Steric Effects on SN2 Reactions

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

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Steric Effect in SN2

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Steric Hindrance Raises Transition State Energy

Steric effects destabilize transition states Severe steric effects can also destabilize

ground state

Very hindered

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Order of Reactivity in SN2 The more alkyl groups connected to the reacting

carbon, the slower the reaction

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Vinyl and Aryl Halides:

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Order of Reactivity in SN2

R Br + Cl-1DMF

R Cl + Br-1

Br Br Br Br

ethyl1.0

propyl0.69

isobutyl0.33

neopentyl0.000006

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The Nucleophile

Neutral or negatively charged Lewis base Reaction increases coordination (adds a new bond) at the

nucleophileNeutral nucleophile acquires positive chargeAnionic nucleophile becomes neutralSee Table 8.2 for an illustrative list

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For example:

Br+ CN-1

C N+ Br-1

CH2 Cl + H2O CH2 OH2 + Cl-1

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Relative Reactivity of Nucleophiles

Depends on reaction and conditions More basic nucleophiles react faster (for similar

structures. See Table 8.3) Better nucleophiles are lower in a column of the

periodic table Anions are usually more reactive than neutrals

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The Leaving Group A good leaving group reduces the energy of activation of a reaction Stable anions that are weak bases (conjugate bases of strong

acids) are usually excellent leaving groups Stronger bases (conjugate bases of weaker acids) are usually

poorer leaving groups

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The Leaving Group

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Poor Leaving Groups

If a group is very basic or very small, it does not undergo nucleophilic substitution.

Converting a poor LG to a good LG:

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The Solvent

Protic solvents (which can donate hydrogen bonds; -OH or –NH) slow SN2 reactions by associating with reactants (anions).

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

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Some Polar Aprotic Solvents

S

O

CH3

H3C

dimethylsulfoxide (DMSO)

CH

O N

CH3

CH3

dimethylformamide(DMF)

PO

N

N

N

H3C CH3

CH3

CH3

CH3H3C

hexamethylphosphoramide(HMPT)

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Summary of SN2 Characteristics: Substrate: CH3->1o>2o>>3o (Steric effect) Nucleophile: Strong, basic nucleophiles favor

the reaction Leaving Groups: Good leaving groups (weak

bases) favor the reaction Solvent: Aprotic solvents favor the reaction;

protic reactions slow it down by solvating the nucleophile

Stereochemistry: 100% inversion

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Prob. 8.8 Arrange in order of SN2 reactivity

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8.14 The SN1 Reaction

Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to the addition of the nucleophile.

Reaction occurs in two distinct steps, while SN2 occurs in one step (concerted).

Rate-determining step is formation of carbocation:

SN1 Reactivity:

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SN1 Energy Diagram

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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 step with the largest energy of activation is the rate-limiting or rate-determining step.

See Figure 11.9 – the same step is rate-determining in both directions)

SN1 Energy Diagram

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Stereochemistry of SN1 Reaction

The planar carbocation intermediate leads to loss of chirality Product is racemic or has some inversion

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Stereochemistry of SN1 Reaction

•Carbocation is usually biased to react on side opposite leaving group because it is unsymmetrically solvated•The second step may occur with the carbocation loosely associated with leaving group.•The result is racemization with some inversion:

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Effects of Ion Pair Formation

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8.15 Characteristics of the SN1 Reaction Tertiary alkyl halides are the most reactive

simple halides by this mechanismControlled by stability of carbocation

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Relative Reactivity of Halides:

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Delocalized CarbocationsDelocalization of cationic charge enhances stabilityPrimary allyl is more stable than primary alkylPrimary benzyl is more stable than allyl

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Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by delocalization of charge (See Figure 11-13) Primary allylic and benzylic are also more

reactive in the SN2 mechanism

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Relative SN1 rates (formolysis):RCl + HCOO-1

Cl

Cl

Cl

Cl

1.0 3550

0.55670

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Cl

Cl

Formation of the allylic cation:

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Effect of Leaving Group on SN1

Critically dependent on leaving group Reactivity: the larger halides ions are better leaving

groups In acid, OH of an alcohol is protonated and leaving

group is H2O, which is still less reactive than halide p-Toluensulfonate (TosO-) is an excellent leaving group

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Nucleophiles in SN1

Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile

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Solvent Is Critical in SN1

The solvent stabilizes the carbocation, and also stabilizes the associated transition state. This controls the rate of the reaction.

Solvation of a carbocation by water

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Polar Solvents Promote Ionization Polar, protic and unreactive Lewis base solvents

facilitate formation of R+ Solvent polarity is measured as dielectric polarization

(P) (Table 11-3)

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Effect of Solvent

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Solvent Polarity

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Effects of Solvent on Energies

Polar solvent stabilizes transition state and intermediate more than reactant and product

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Summary of SN1 Characteristics: Substrate: Benzylic~allylic>3o >2o

Nucleophile: Does not affect reaction (although strong bases promote elimination)

Leaving Groups: Good leaving groups (weak bases) favor the reaction

Solvent: Polar solvents favor the reaction by stabilizing the carbocation.

Stereochemistry: racemization (with some inversion)

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Prob. 8.9 Arrange in order of SN1 reactivity

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Problem 8.10: SN1 or SN2?

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Problem 8.11: SN1 or SN2?

Biological Substitution Reactions

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Biological Substitution Reactions

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Biological Substitution Reactions

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8.16 Alkyl Halides: Elimination Elimination is an alternative pathway to substitution Elimination is formally the opposite of addition, and

generates an alkene It can compete with substitution and decrease yield,

especially for SN1 processes

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Zaitsev’s Rule for Elimination Reactions (1875) In the elimination of HX from an alkyl halide, the more

highly substituted alkene product predominates

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Mechanisms of Elimination Reactions Ingold nomenclature: E – “elimination” E1 (1st order): X- leaves first to generate a

carbocation a base abstracts a proton from the carbocation

E2 (2nd order): Concerted transfer of a proton to a base and departure of leaving group

E1cb : Carbanion intermediate is formed in the rate-determining step

E1 mechanism: starts out like SN1

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E2 mechanism: concerted

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E1cb: common in biochemical reactions

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8.17 The E2 Reaction Mechanism

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

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E2 Reaction Kinetics

One step (concerted): rate law dependent on base and alkyl halide

Rate = k[R-X][B] Reaction goes faster with stronger

base, better leaving group

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Kinetic Isotope Effect Substitute deuterium for hydrogen at position Effect on rate is kinetic isotope effect (kH/kD = deuterium isotope

effect) Rate is reduced in E2 reaction

Heavier isotope bond is slower to breakShows C-H bond is broken in or before rate-limiting step

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kH/kD

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Geometry of Elimination – E2 Antiperiplanar allows orbital overlap and

minimizes steric interactions

E2 Stereochemistry

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Comparison of SN2 and E2:

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

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

1-bromoethene

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Anti periplanar geometry

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8.18 Elimination From Cyclohexanes Abstracted proton and leaving group should align

trans-diaxial to be anti periplanar (app) in approaching transition state (see Figures 11-19 and 11-20)

Equatorial groups are cannot be in proper alignment

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Elimination From Cyclohexanes

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Axial vs. Equatorial Leaving Groups

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8.19 The E1 Reaction Competes with SN1 and E2 at 3° centers Rate = k [RX]

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Stereochemistry of E1 Reactions

E1 is not stereospecific and there is no requirement for alignment

Product has Zaitsev orientation because the step that controls product formation is loss of proton after formation of carbocation

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Comparing E1 and E2

Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation; E2 may not due to stereospecificity E1 is favored in protic solvents; competes with SN1

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Comparing E1 and E2

E1cb:

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A biochemical example (from fat biosynthesis):

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Reactivity Summary: SN1, SN2, E1, E2

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General Pattern by Substrate

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Primary alkyl halides (SN2 vs E2)

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Secondary alkyl halides (SN2 vs E2)

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Tertiary alkyl halides (SN1/E1 vs E2)

Prac. Problem

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Answers

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Problem 8.12

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Problem 8.13: This halide does not undergo SN1 or SN2 reactions. Why?

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It also fails to eliminate HBr under basic conditions. Why?

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