TS. Trần Thượng Quảng Bộ Môn Hóa Hữu cơ Viện Kỹ Thuật Hóa học HUST Phản ứng hóa học của ankyl halogenua: Phản ứng thế nucleophil và tách loại TS. Trần Thượng Quảng Bộ Môn Hóa Hữu cơ Viện Kỹ Thuật Hóa học HUST

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

Ankyl halogenua phản ứng với tác nhân nucleophil và bazơ Các nucleophil có tính bazơ mạnh theo Brønsted gây ra phản ứng tách loại

Phản ứng thế vs. Phản ứng tách loại

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.

Substitution Mechanisms SN1 Two steps with carbocation intermediate Occurs in 3°, allyl, benzyl SN2 Concerted mechanism - without intermediate Occurs in primary, secondary

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

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

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=substitution N (subscript) = nucleophilic 2 = both nucleophile and substrate in rate-determining step (bimolecular)

SN2 Process

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

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)

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-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

Steric Effect in SN2

Steric Hindrance Raises Transition State Energy Very hindered Steric effects destabilize transition states Severe steric effects can also destabilize ground state

Order of Reactivity in SN2 The more alkyl groups connected to the reacting carbon, the slower the reaction

Vinyl and Aryl Halides:

Order of Reactivity in SN2

The Nucleophile Neutral or negatively charged Lewis base Reaction increases coordination (adds a new bond) at the nucleophile Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral See Table 8.2 for an illustrative list

For example:

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

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

The Leaving Group

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:

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

Some Polar Aprotic Solvents

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

Prob. 8.8 Arrange in order of SN2 reactivity

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:

SN1 Energy Diagram

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

Stereochemistry of SN1 Reaction The planar carbocation intermediate leads to loss of chirality Product is racemic or has some inversion

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:

Effects of Ion Pair Formation

8.15 Characteristics of the SN1 Reaction Tertiary alkyl halides are the most reactive simple halides by this mechanism Controlled by stability of carbocation

Relative Reactivity of Halides:

Delocalized Carbocations Delocalization of cationic charge enhances stability Primary allyl is more stable than primary alkyl Primary benzyl is more stable than allyl

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

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

Formation of the allylic cation:

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

Nucleophiles in SN1 Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile

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

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)

Effect of Solvent

Solvent Polarity

Effects of Solvent on Energies Polar solvent stabilizes transition state and intermediate more than reactant and product

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)

Prob. 8.9 Arrange in order of SN1 reactivity

Problem 8.10: SN1 or SN2?

Problem 8.11: SN1 or SN2?

Biological Substitution Reactions

Biological Substitution Reactions

Biological Substitution Reactions

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

Zaitsev’s Rule for Elimination Reactions (1875) 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 (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

E2 mechanism: concerted

E1cb: common in biochemical reactions

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

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

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 break Shows C-H bond is broken in or before rate-limiting step

kH/kD

Geometry of Elimination – E2 Antiperiplanar allows orbital overlap and minimizes steric interactions

E2 Stereochemistry

Comparison of SN2 and E2:

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

Anti periplanar geometry

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

Elimination From Cyclohexanes

Axial vs. Equatorial Leaving Groups

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

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

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

Comparing E1 and E2

E1cb:

A biochemical example (from fat biosynthesis):

Reactivity Summary: SN1, SN2, E1, E2

General Pattern by Substrate

Primary alkyl halides (SN2 vs E2)

Secondary alkyl halides (SN2 vs E2)

Tertiary alkyl halides (SN1/E1 vs E2)

Prac. Problem

Answers

Problem 8.12

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

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