các loại phản ứng hữu cơ

Substitution and Elimination at Csp3–X Bonds• In a nucleophilic substitution reaction, a nucleophile– electrophile bond replaces the electrophile–X bond... Substitution reactions at 1° a

PHẢN ỨNG HỮU CƠ

PHÂN LOẠI PHẢN ỨNG HỮU CƠ

4 loại chính:

1 Phản ứng thế (Substitution)

2 Ph ả n ứ ng tách (elimination)

PHÂN LOẠI PHẢN ỨNG HỮU CƠ

3 Ph ả n ứ ng c ộ ng (addition)

PHÂN LOẠI PHẢN ỨNG HỮU CƠ

DỊ LY VÀ ĐỒNG LY

1 SỰ DỊ LY (Heterolysis)

■ Thường xảy ra đối với các liên kết bị phân cực

■ Cần một tác nhân hỗ trợ để có thể tách rời hai

Đồng ly

Dị ly

Dị ly

Bond-Making

1 Cơ chế phân cực (polar mechanism)

- Basic conditions

- Acidic conditions

2 Cơ chế gốc tự do (radical mechanism)

3 Cơ chế đồng bộ (pericyclic mechanism)

CƠ CHẾ PHẢN ỨNG

Polar Reactions under Basic Conditions

1 Substitution and Elimination at C(sp 3 )–X

1.1 Substitution by SN2 Mechanism

1.2 β-Elimination by the E2 and E1cb Mechanism

1.3 Substitution by SRN1 Mechanism

2 Addition of Nucleophiles to Electrophilic π-Bonds

2.1 Addition to Carbonyl Compounds

2.2 Conjugate Addition; The Michael Reaction

3 Substitution at C(sp 2 )–X Bonds

3.1 Substitution at Carbonyl C

3.2 Substitution at Alkenyl and Aryl C

3.3 Metal insertion; Halogen-Metal Exchange

4 Base-Promoted Rearrangements

5 Two Multistep Reactions

Polar Reactions under Basic Conditions

1 Substitution and Elimination at C(sp3)–X

Electrophiles that have leaving groups (X) attached to C(sp3) usually undergo

substitution or elimination reactions

1 Substitution and Elimination at C(sp3)–X Bonds

• In a nucleophilic substitution reaction, a nucleophile–

electrophile bond replaces the electrophile–X bond

• In an elimination

reaction, the leaving

group X (with its

1.1 Substitution by SN2 Mechanism

• A nucleophile is a compound that has a relatively

high energy pair of electrons available to make a newbond

• A nucleophilic atom may be neutral or negativelycharged

• There are three classes of nucleophiles:

– lone-pair nucleophiles,

– σ-bond nucleophiles,

– π-bond nucleophiles

• A nucleophile is a compound that has a relatively

high energy pair of electrons available to make a newbond

• A nucleophilic atom may be neutral or negativelycharged

• There are three classes of nucleophiles:

– lone-pair nucleophiles,

– σ-bond nucleophiles,

– π-bond nucleophiles

• Lone-pair nucleophiles: contain atoms with lone electron pairs The lone pair is used to make a new bond to an electrophilic atom.

• Alcohols (ROH), alkoxides (RO-), amines (R3N), metal amides (R2N - ), halides (X - ), thiols (RSH), sulfides (R2S), and phosphines (R3P) are all examples of lone-pair nucleophiles, as are the O atoms of carbonyl compounds (X2C=O) When these compounds act as nucleophiles, the

formal charge of the nucleophilic atom is increased by 1

in the product.

NUCLEOPHILICITY

NUCLEOPHILICITY

COMMON SOLVENTS

• σ-bond nucleophiles: contain a bond between a nonmetal and a metal The formal charge on the nucleophilic atom does not change; the metal increases its formal charge by 1.

• The nucleophilic atom may be a heteroatom (as in NaNH2 or KOH), carbon (as in Grignard reagents (RMgBr), organolithium reagents (RLi), and Gilman reagents (R2CuLi), which have C–Mg, C–Li, and C–Cu bonds, respectively), or hydrogen (as in the complex metal hydrides NaBH4 and LiAlH4).

• π-bond nucleophiles use the pair of electrons in a bond,usually a C=C bond, to form a bond between one of theatoms in the bond and the electrophilic atom

• The formal charge and total electron count of thenucleophilic atom of the bond do not change, but the

other atom of the bond is made electron-deficient, and

its formal charge increases by 1

• The bonds of simple alkenes and arenes are weaklynucleophilic; bonds that are directly attached toheteroatoms, such as in enolates, enols, enol-ethers andenamines are much better nucleophiles

• Lone-pair nucleophiles: the most common participants in SN2

• Sigma-bond nucleophiles may also participate in SN2

• Others: the enamines, (R2N–CR=CR2), which are sufficiently nucleophilic at the position to attack particularly reactive alkyl halides such as CH3I and allylic and benzylic bromides, and enolates (O̶–CR= CR2), which react with many alkyl halides.

• Electrophiles with allylic leaving groups can undergoeither SN2 or S N 2´ substitution.

• In SN2´ substitution, the lone pair on Nu moves toform a bond to the γ-carbon of the allylic system

1.1 Substitution by SN2 Mechanism

NHÓM XUẤT

Được tách ra khỏi phân tử dưới dạng

phân tử trung hòa điện hoặc ion âm.

Nhóm xuất tốt: ion có khả năng bền

vững hóa điện tích âm của nó: base yếu

Tính base : F− >> Cl− > Br − > I−

Khả năng xuất : I− > Br − > Cl− >> F−

NHÓM XUẤT TỐT

SO

O

−

SO

Alkanesulfonate ion Alkyl sulfate ion

p-Toluenesulfonate ion Triflate ion

CH3 CH3 CH3 Nu

 Substitution reactions at 1° and 2° (but not

3°) C(sp3) usually proceed by the SN2 mechanism under basic or neutral conditions:

 The stereochemistry of C is inverted.

 The nucleophile may be anionic or neutral, and

the electrophile may be neutral or cationic.

• 1.1 Substitution by SN2 Mechanism

1.1 Substitution by SN2 Mechanism

1.1 Substitution by SN2 Mechanism

1.1 Substitution by SN2 Mechanism

CHẤT THÂN HẠCH

NHÓM XUẤT

● Tương tự, do chướng ngại lập thể,

vinylic halide và aryl halide hoàn

toàn không cho phản ứng thế SN2.

CẤU TRÚC ALKYL HALIDE

1.1 Substitution by SN2 Mechanism

SỰ BỀN VỮNG HÓA TRẠNG THÁI CHUYỂN TIẾP

Chướng ngại lập thể trong S N 2

● Methyl: CH3–X : rất nhanh

● Alkyl bậc 1 ° : RCH2–X : nhanh

● Alkyl 2 ° : R2CH−X : chậm

● Alkyl 3 ° : R3C–X: k.p.ư

Chướng ngại lập thể trong SN2

C C

Cl

R R

Ảnh hưởng của dung môi

● Dung môi phân cực

● Trong dung dịch: chất thân hạch và cả tạp

chất kích động sẽ bị solvat hóa :

► Bền vững hóa trạng thái chuyển tiếp

→ Tăng vận tốc phản ứng

► Cản trở sự tiếp cận tâm carbon thân

điện tử của chất thân hạch

→ Giảm tốc độ phản ứng thế SN2

H OR

Ảnh hưởng của dung môi

Ảnh hưởng của dung môi

Chất thân hạch NaBr trong dung môi acetone

Dung môi trong phản ứng SN2

 Solvate hóa tốt các cation kim loại

 Solvat hóa rất kém các anion

YẾU TỐ LẬP THỂ TRONG SN2

Sản phẩm tạo thành có sự

đảo ngược cấu hình so với

ban đầu

Cl − +

cis-1-Chloro-3-methylcyclopentane

trans-3-methylcyclopentanol

SN2 substitution can occur at elements other than

C For example, substitution at a stereogenic S atom leads to inversion of configuration.

1.1 Substitution by SN2 Mechanism

• Not all substitution reactions under basic conditionsoccur with simple inversion Sometimes, nucleophilicsubstitution at stereogenic C proceeds with retention

of configuration In such a reaction, two sequentialnucleophilic substitutions have usually occurred

1.1 Substitution by SN2 Mechanism

1.2 β-Elimination by the E2 and E1cb Mechanisms

• C(sp3)–X electrophiles can undergo β-eliminationreactions as well as substitutions

• Elimination reactions proceed by the E2 or E1cb

mechanism under basic conditions

• Because the H–C and the C–X bonds breaksimultaneously in the E2 mechanism, there is a

stereoelectronic requirement that the orbitals making

up these two bonds be periplanar:

1.2 β-Elimination by the E2 and E1cb Mechanisms

• In six-membered rings, the antiperiplanar requirementfor E2 elimination is satisfied when both the leavinggroup and the adjacent H atom are axial.

Example: only one C–H bond is antiperiplanar to theC–Cl bond in the reactive conformation of menthylchloride, so only one product is obtained

1.2 β-Elimination by the E2 and E1cb Mechanisms

• In the diastereomer neomenthyl chloride: the C–Clbond is antiperiplanar to two C–H bonds in the lowestenergy conformation so two products are obtainedupon E2 elimination.

1.2 β-Elimination by the E2 and E1cb Mechanisms

• Alkenyl halides or alkenyl ethers (enol ethers) also undergo β-elimination readily: either an alkyne or an allene may be obtained.

1.2 β-Elimination by the E2 and E1cb Mechanisms

• E2 eliminations, in which a bond is interposedbetween the two C atoms at which bond breakingoccurs, are also seen In the following example, thebase is F, and a Me3Si group replaces the usual H.

1.2 β-Elimination by the E2 and E1cb Mechanisms

 β-Elimination sometimes gives high-energy species.Under very strongly basic conditions, halobenzenesundergo β-elimination to give benzynes, compoundsthat are highly strained and reactive.

 β-Elimination from acyl chlorides occurs undermildly basic conditions to give ketenes.

1.2 β-Elimination by the E2 and E1cb Mechanisms

• When the H is particularly acidic (usually because it

is adjacent to a carbonyl) and the leaving group isparticularly poor (especially OH and OR), a two-stepmechanism called E1cb operates

1.2 β-Elimination by the E2 and E1cb Mechanisms

The E1cb elimination is the usual mechanism bywhich a hemiacetal is converted to a carbonylcompound under basic conditions.

1.2 β-Elimination by the E2 and E1cb Mechanisms

Predicting Substitution vs Elimination

Two factors largely determine the course of the reaction:

1 The nucleophilicity and basicity of the lonepair-bearing

compound,

2 The identity of the substrate: Me or Bn, 1°, 2°, or 3°

halide

Phản ứng Thế hay Khử ?

Chướng ngại lập thể

Tính thân hạch và tính base

Nhiệt độ

CHƯỚNG NGẠI LẬP THỂ

E2 hay SN2 ???

E2 hay SN2 ???

TÍNH BASE

Nhiệt độ

Ph ản ứng tách : ∆S > 0

► ∆G < 0 khi T càng lớn

SN2 hay E2 ?

 Chất thân hạch mạnh, tính base yếu sẽ

ưu tiên phản ứng thế thân hạch : I–, Br–,

HS–, –CN và CH3COO–

 Chất thân hạch kích thước cồng kềnh sẽ ưu tiên phản ứng tách : KO(CH3)3, DBU, DBN

SN2 hay E2 ?

SN2 hay E2 ?

Alkyl halide 3° : Base mạnh : Cơ chế E2

SN2 hay E2 ?

Alkyl halide 1° :

 Chất thân hạch mạnh: SN2

SN2 hay E2 ?

Alkyl halide 1° :

 Base mạnh, cồng kềnh: E2

SN2 hay E2 ?

Alkyl halide 2° :

 Base mạnh, tính thân hạch mạnh :

Cơ chế SN2 và E2

SN2 hay E2 ?

Alkyl halide 2° : Base mạnh, cồng kềnh :

Cơ chế E2

1.3 Substitution by the SRN1 Mechnism

The S RN 1 mechanism can operate at C(sp 3 ) under basic conditions.

1.3 Substitution by the SRN1 Mechnism

 The best nucleophiles for the S RN 1 mechanism can make a relatively stable radical in the initiation part.

 The best electrophiles for the S RN 1 mechanism are able to delocalize the odd electron in the radical anion.

1.4 Substitution by the Elimination–Addition Mechanism

 The elimination–addition mechanism for

substitution is reasonable only when elimination gives an alkene that is a π-bond electrophile at the C atom to which the leaving group was originally attached

 If a substitution reaction gives a stereochemical

result other than inversion or involves a very hindered substrate: elimination–addition or SRN1 should be considered.

Is an elimination–addition mechanism reasonable for the following reactions? Draw the most reasonable mechanism for each one.

2.1 Addition to Carbonyl Compounds

 Under basic conditions, carbonyl compounds

are electrophilic at the carbonyl carbon and nucleophilic at the α–carbons (if they have H atoms attached).

 The thermodynamic stabilities of carbonyl

compounds are directly related to the stabilities of their R2C+─O− resonance structures.

2 Addition of Nucleophiles to Electrophilic π-Bonds

2.1 Addition to Carbonyl Compounds

The order of thermodynamic stabilities

of the common types of carbonyl compounds is : RCOCl ( acyl chlorides ) < RCO2COR ( acid anhydrides ) < RCHO ( aldehydes ) < R2CO ( ketones ) < RCO2R ( acids, esters ) < RCONR2( amides ) < ROCO2R ( carbonates ) < ROCONR ( urethanes/carbamates )< R2NCONR2

( ureas ) < RCO2− ( carboxylate salts )

2.1 Addition to Carbonyl Compounds

Grignard reagents and organolithium compounds are very strong bases toward 1,3-dicarbonyl and steric hindrance carbonyl compounds.

When the α-carbon of an aldehyde or ketone is

a stereocenter: Felkin–Anh selectivity

2.1 Addition to Carbonyl Compounds

 When a carbonyl compound with two α-hydrogen

atoms (R1CH2COX) undergoes an aldol reaction with

an aldehyde R2CHO: syn aldol.

2.1 Addition to Carbonyl Compounds

When an enantiopure, easily replaced X group is used: both new stereocenters in the aldol product to form with very high stereoselectivity, it is called a chiral auxiliary

2.1 Addition to Carbonyl Compounds

2.2 Conjugate Addition: The Michael Reaction

Alkenes and alkynes that are substituted with withdrawing groups such as carbonyl, nitro, and sulfonylgroups are electrophilic

electron-The most important kinds of conjugate additionreactions are Michael reactions, which involve theaddition of C nucleophiles to C––C bonds

The nucleophiles are often 1,3-dicarbonyl compounds such as malonates, cyanoacetates, β - ketoesters, and 1,3-diketones, but simple carbonyl compounds may also be used Only catalytic amounts of base are usually required

2.2 Conjugate Addition: The Michael Reaction

Often, the Michael reaction is followed by an aldol reaction, a substitution, or another Michael reaction.

For example: the Robinson annulation consists of a Michael reaction, an aldol reaction, and a dehydration (β− elimination).

2.2 Conjugate Addition: The Michael Reaction

Polar Reactions under Basic Conditions

1 Substitution and Elimination at C(sp3)–X

2 Addition of Nucleophiles to Electrophilic π-Bonds

2.1 Addition to Carbonyl Compounds

2.2 Conjugate Addition; The Michael Reaction

3 Substitution at C(sp2)–X Bonds

3.1 Subtitution at Carbonyl C

3.2 Subtitution at Alkenyl and Aryl C

3.3 Metal insertion; Halogen-Metal exchange

3.1 Substitution at Carbonyl C

The reaction of alcohols with enolizable acyl

chlorides or anhydrides can proceed by two

different mechanisms:

- The addition–elimination mechanism:

3.1 Substitution at Carbonyl C

- A two-step: elimination–addition mechanism In theelimination step, β-elimination occurs by an E2mechanism to give a ketene, a very reactive compoundthat is not usually isolable In the addition step, thealkoxide adds to the electrophilic carbonyl C of theketene to give the enolate of an ester.

3.1 Substitution at Carbonyl C

A nucleophilic catalyst such as DMAP(4-dimethylaminopyridine) is added to acceleratethe acylation of alcohols ROH with acyl chlorides.

3.1 Substitution at Carbonyl C

Phản ứng ngưng tụ Claisen

H-α của ester có tính acid yếu hơn H-α của dehyde hoặc ketone.

107

Cơ chế phản ứng ngưng tụ Claisen

108

The Claisen and Dieckmann condensations : reactions in which an

ester enolate acts as a nucleophile toward an ester:

A stoichiometric amount of base is required for this reaction, because the product is a very good acid, and it quenches the base catalyst This quenching reaction drives the overall reaction to completion.

3.1 Substitution at Carbonyl C

The Claisen condensation is especially useful when one of the esters

is nonenolizable (e.g., diethyl oxalate, ethyl formate, or diethyl carbonate)

3.1 Substitution at Carbonyl C

Like aldol reactions, the addition of enolates to esters is reversible 1,3-Dicarbonyl compounds that cannot be deprotonated cleave readily

to give two simple carbonyl compounds under basic conditions The cleavage occurs by addition–elimination, and an enolate acts as a leaving group:

3.1 Substitution at Carbonyl C

 Grignard reagents, organolithium compounds, and complex

metal hydrides react with esters to give alcohols.

 The ketone or aldehyde is more reactive than the starting

material toward the nucleophile, though, so another equivalent

of nucleophile adds to it to give an alcohol after workup:

3.1 Substitution at Carbonyl C