δ X δ electrophilic site C - Yonsei University€¦ · Ch.11 Nucleophilic Substitutions and...

Ch.11 Nucleophilic Substitutions and Eliminations

X

Cδ+

δ-

electrophilic site

XCNu- Nu C

- nucleophilic substitution and base-induced elimination of alkyl halides

Substitution


H

C

X

C

B-

C C B-H + X-+

Elimination


11.1 The Discovery of Walden Inversion

In 1896, Walden discovered pure enantiomeric (+)- and (-)-malic acids could be interconverted by a series of simple substitution reactions.

HOOCCOOH

OH

(-)-Malic acid

[α]D = -2.3o

PCl5 HOOCCOOH

Cl(+)-Chlorosuccinic acid

Ag2O, H2O

HOOCCOOH

OH

(+)-Malic acid

[α]D = +2.3o

PCl5HOOC

COOH

Cl(-)-Chlorosuccinic acid

Ag2O, H2O

Et2O

Et2O

Walden's cycle of reactions interconverting (+)- and (-)-malic acids

necleophilic substitution reactions


11.2 Stereochemistry of Nucleophilic Substitution

In 1920s, Kenyon and Philips: mechanism of nucleophilic substitution reactions

YR

Substitution

Nu- NuR + Y-

Y = Cl, Br, I, OTs

Nu = nucleophile S CH3O

OO = OTs


Interconverting (+)- and (-)-1-phenyl-2-propanol

OH H

(+)-1-Phenyl-2-propanol[α]D = +33.0

o

OH Ts

[α]D = +31.1o

TsCl

pyridine+ HCl

HO

[α]D = -7.06o

CH3COO-

+ -OTs

O CH3

OH

CH3O

HO

(-)-1-Phenyl-2-propanol[α]D = -33.2

o[α]D = -31.0

o

+HClTsCl

pyridine

CH3COO-

+-OTs

H2O, -OH

+ CH3COO-

H

HOTs

[α]D = +7.0o


Inversion of stereochemistry in the nucleophilic substitution step

OH Ts

[α]D = +31.1o

HO

[α]D = -7.06o

CH3COO-

+ -OTs

O CH3Inversion of configuration


11.3 Kinetics of Nucleophilic Substitution

Reaction rate: a useful tool in the mechanism studies

BrH3C OHH3C + Br-HO- +

Kinetics: measure the relationship between reaction rate and reactant concentrations

reaction rate = rate of disappearance of reactant

= k x [RX] x [-OH] k = a constant

Second-order reaction: the reaction rate is linearly dependent on the concentration of two species


11.4 The SN2 Reaction

Nucleophilic substitution reactions:

1. Inversion of stereochemistry at the carbon center2. The reaction show second-order kinetics

Rate = k x [RX] x [Nu-]

SN2 reaction: substitution, nucleophilic, bimolecular; bimolecular means that two molecules, nucleophile and alkyl halide, take part in the step whose kinetics are measured.


BrC

H

H3CH3CH2C

HO C

H

CH3CH2CH3

BrC

A

BC

HOδ- δ-

HO-

In 1937, Hughes and Ingold; suggested a SN2 mechanism

- Inversion of stereochemistry: back-side attack of nucleophile from a direction 180o away from the leaving group

- Second-order kinetics: SN2 reaction occurs in a single step and two molecules are involved in the step


Brno substitution reaction with -OH

• evidence for back-side SN2 displacement

Why ?


11.5 Characteristics of the SN2 Reaction

The effects of changes in reactant and transition-state energy levels on reaction rate.

∆G

∆G∆G ∆G

A higher reactant energy level: faster reaction (smaller ∆G‡)

A higher transition state energy level: slower reaction (higher ∆G‡)

• reaction rate is determined by ∆G‡

• reactant and transition energy levels can affect the reaction rate


A. The Substrate: Steric Effects in the SN2 Reaction

Since the SN2 transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom, stericallyhindered alkyl halides are less reactive.

SN2 variables

BrC

H3C

H3C

H3CBrC

H3C

H3C

HBrC

H

H3C

H


The Substrate: Steric Effects in the SN2 Reaction

SN2 reactions can occur only at relatively unhindered sites: methyl halides, 1o halides, a few simple 2o halides

CH

HH3CC

H

CH3H3CC

CH3

CH3H3C

primarysecondarytertiary

reactivity

CH

HH

methyl

more reactiveless reactive

BrBrBrBr CCH3

CH3H3C

neopentyl

CH2 Br

40,000500


sp2 hybrid carbons: vinylic, aryl halides are unreactive toward SN2 reaction

• the approach from the back side in the C=C double bond plane is inaccessible

C CR R

R Cl

Nu-X Cl

Nu-

X


B. The Attacking Nucleophile

Nucleophiles: have an unshared pair of electrons (Lewis base); neutral or negatively charged

Nu:- + R Y +R Nu Y:-

Negatively charged Nu:-

neutral

Nu: + R Y +R Nu Y:-

Neutral Nu:-

positively charged


H3C Br+Nu:- Nu CH3 + Br-

CH3S

HS

N C

N N N

I

CH3O

HO

Cl

H3N

CH3CO2(CH3)3N

H

Methanethiolate

Hydrosulfide

Cyanide

Azide

Iodide

Methoxide

Hydroxide

Chloride

Ammonia

Acetate

trimethyl amine

Hydride

CH3S

HS

N C

N N N

I

CH3O

HO

Cl

H3N

CH3CO2(CH3)3N

H

CH3CH3

CH3

CH3CH3

CH3

CH3

CH3

CH3CH3

CH3

CH3

Br-

Br-

Nucleophiles


Nucleophilicity: depends on the substrate, the solvent, the reactant concentration...

nucleophilicity

H3C Br+Nu:- Nu CH3 + Br-

HSN CICH3OHOClH3NCH3CO2H2O

1 500 700 1,000 16,000 25,000 100,000 125,000 125,000

nucleophilicityless

nucleophilicmore

nucleophilic

Trends in nucleophilicity: complete explanations aren't known


• Nucleophilicity roughly parallels basicity:because "nucleophilicity" measures the affinity of a Lewis base for a carbon atom in the SN2 reaction, and "basicity" measures the affinity of a base for a proton

CH3O HO CH3CO2 H2ONucleophileRate of SN2 reaction with CH3BrpKa of conjugate acid

25

15.5

16 0.5 0.001

15.7 4.7 -1.7

Correlation of Basicity and Nucleophilicity


• Nucleophilicity usually increases going down a column of the periodic table: due to increased polarizability

HS- > HO-I- > Br- > Cl-

• Negatively charged nucleophiles are usually more reactive than neutral ones.; As a result, SN2 reactions are often carried out under basic conditions rather than neutral or acidic conditions.

HO- > H2O


C. The Leaving Group

Good leaving groups:- well-stabilized negative charge; stable anions- weaker base: the stability of an anion is inversely related to the basicity

leaving group ability

OH-, OR-


Poor leaving groups: F-, OH-, OR-, NR2- are not displaced by nucleophiles

R F R OH R OR' R NH2

YC Nu CYCNuδ- δ-

Nu:- + Y:-

Transition State(Negative charge is delocalized

over both Nu- and Y

The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction


D. The Solvent

Protic solvents; those contain -OH or -NH groups- are generally the worst solvent

protic solvents: CH3OH, EtOH

X:-H

H HH

OR

OR

OR

ROA solvated anion

(reduce nucleophilicity due to enhanced ground-state stability)

Solvation: solvent molecules hydrogen bond to the nucleophile, orienting themselves into a "cage" around it and thereby lowering its reactivity


n-Bu-Br + N3- n-Bu-N3 + Br

-

solvent CH3OH H2O DMSO DMF CH3CN HMPA

relativereactivity 1 7 1,300 2,800 5,000 200,000

solvent reactivitymore

reactiveless

reactive

Polar aprotic solvents; have strong dipoles but no -OH or -NH groups are the best for SN2 reaction- CH3CN, DMF (Me2NCHO), DMSO (Me2SO), HMPA [((Me2N)3PO]- increased solubility of salts- solvate metal cations rather than nucleophiles→ the bare unsolvatedanions have greater nucleophilicity


A Summary of SN2 Reaction Characteristics

Substrates Steric hindrance raises the energy of the transition state, thus increasing ∆G‡ and decreasing the reaction rate. As a result, SN2 reactions are best for methyl and primary substrates.

Nucleophile More reactive nucleophiles are less stable and have a higher ground-state energy, thereby decreasing ∆G‡ and increasing the reaction rate. Basic, negatively charged nucleophiles are more reactive than neutral ones.



Leaving group

Good leaving groups (more stable anions) lower the energy of the transition state, thus decreasing ∆G‡and increasing the reaction rate.

Solvents Protic solvents solvate the nucleophile, thereby lowering its ground-state energy, increasing ∆G‡, and decreasing the reaction rate. Polar aprotic solvents surround the accompanying cation but not the nucleophilic anion, thereby raising the ground-state energy of the nucleophile, decreasing ∆G‡, and increasing the reaction rate.


Reaction energy diagram;- substrate and leaving group affect the transition states- nucleophile and solvent affect the reactant ground states

hinderedsubstrate

unhinderedsubstrate

poor leavinggroup

good leavinggroup


Reaction energy diagram;- substrate and leaving group affect the transition states- nucleophile and solvent affect the reactant ground states

goodnucleophile

poornucleophile

polar aproticsolvent

proticsolvent


11.6 The SN1 Reaction

CH

HH3C C

H

CH3H3C C

CH3

CH3H3C

primary secondary tertiary

reactivity

CH

HH

methyl

more reactiveless reactive

Br Br Br Br

121


11.7 Kinetics of the SN1 Reaction

reaction rate = rate of disappearance of alkyl halide

= k x [RX] k = a constant

First-order reaction: the reaction rate is linearly dependent on the concentration of only one species; the concentration of the nucleophiledoes not appear in the rate expression

Rate-determining step (rate-limiting step): the slowest step in a successive steps of a multi-step reaction- no reaction can proceed faster than its rate-determining step- the overall reaction rate measured in kinetic experiments is determined by the height of the highest energy barrier


∆G

1st step is RDS

∆G1

2nd step is RDS


C

CH3

CH3

H3C Br

mechanism of SN1 reaction

C

CH3

CH3

H3C

+ Br-

OH2RDS

fastC

CH3

CH3

H3C OH

H

C

CH3

CH3

H3C O H

OH2

+ H3O+

• spontaneous dissociation of the leaving group occurs in a slow, rate-limiting step to generate a carbocation intermediate


∆G

RX + Nu:-

R+ + X-

RNu+ X:-

• spontaneous dissociation of the leaving group occurs in a slow, rate-limiting step to generate a carbocation intermediate


11.8 Stereochemistry of the SN1 Reaction

X

A

CB

A

CB

Nu- Nu-

Nu

A

CBNu

A

C B

planar, achiral50% inversion of configuration

50% retention ofconfiguration

carbocation intermediate: sp2-hybridized, planar, achiral


CH3Cl H2O

EtOH

CH3HO OHH3C+

40% R(retention)

(R) 60% S(inversion)

- 80% racemized- 20% inverted

Only few SN1 reactions occur with complete racemization.Most give a minor (0-20%) excess of inversion.

Generally, SN1 reaction of enantiomerically pure substrates lead to racemicproducts.


Ion pair (proposed by Saul Winstein): dissociation of the substrate occurs to give a structure in which the two ions are still loosely associated and in which the carbocation is effectively shielded from nucleophilicattack on one side by the departing anion.

X

A

CB

A

CB

Nu- Nu

A

C B

ion pair

X

shieldedopen

more inversion product


11.9 Characteristics of the SN1 Reaction

• factors that lower ∆G‡, either by lowering the energy level of the transition state or by raising the energy level of the ground state, favor SN1 reactions

A. The Substrate

Hammond postulate: any factor that stabilizes a high-energy intermediate should stabilize the transition state leading that intermediate.; the rate-limiting step in the SN1 reaction is carbocation-formation step; The more stable the carbocation intermediate, the faster the SN1 reaction.


allylic carbocation

CH2 H2C

Allylic, benzylic carbocation: resonance stabilized,

benzylic carbocation

CH2 CH2 CH2 CH2


Allylic, benzylic substrates: highly reactive in SN2 and SN1 reactions

Carbocation stability:

~


B. The Leaving Group

- same reactivity as in SN2 reaction

leaving group ability

H2O

leaving group reactivityless

reactivemore

reactive

Cl- Br- I- TsO-

- neutral water is leaving group in SN1 reaction of alcohols under acidic conditions


C

CH3

CH3

H3C OH

mechanism of SN1 reaction

+ Br-

C

CH3

CH3

H3C

C

CH3

CH3

H3C Br

+ OH2

HBrC

CH3

CH3

H3C OH

HBr-

RDS

fast


C. The Nucleophile

• nucleophile is not involved in the RDS, thus does not affect the reaction rate

C

CH3

CH3

H3C OH C

CH3

CH3

H3C Br+ HX + H2O

same rate for X = Cl, Br, I

• Neutral nucleophiles are just as effective as negatively charged ones, so SN1 reactions frequently occur under neutral or acidic conditions. (not under basic conditions)


D. The Solvent

Solvent effectSN2 reaction: due largely to stabilization or destabilization of the nucleophile reactantSN1 reaction: due largely to stabilization or destabilization of the transition state

HO

H

C

HO H

HOH

HO

HHO H

HOH

Solvation of carbocation: the electron rich oxygen atoms of solvent molecules orient around the positively charged carbocation and thereby stabilize it.


Dielectric polarization (P): express solvent polarity; measure the ability of a solvent to act as an insulator of electric charges

Aprotic solvents

HexaneBenzeneDiethyl etherChloroformHMPADMFDMSO

1.9 2.3 4.3 4.8303848

Protic solvents

Acetic acidEthanolMethanolFormic acidWater

6.224.333.658.080.4

Polar solvents (water, methanol, DMSO) are good at solvating ions,nonpolar ether, hydrocarbon solvents are very poor at solvating ions


• SN1 reactions take place much more rapidly in polar solvents than in nonpolar solvents

C

CH3

CH3

H3C Cl C

CH3

CH3

H3C OR+ ROH + HCl

relaticereactivity

EtOH 40% H2O / 60% EtOH80% H2O / 20% EtOH Water

1 100 14,000 100,000


Large solvent effect but different reasons;

∆G∆G

R+

nonpolarsolvent

polarsolvent RNu + :X-

RX + :Nu-

The effect of solvent on SN1 reaction

SN1 reaction: favored in protic solvents beacuse the transition-state energy leading to carbocation intermediate is lowered by solvation


Large solvent effect but different reasons;

polar aproticsolvent

proticsolvent

The effect of solvent on SN2 reaction

SN2 reaction: disfavored in protic solvents beacuse the ground-state energy of the attacking nucleophile is lowered by solvation



Substrates The best substrates yield the most stable carbocations. As a result, SN1 reactions are best for tertiary, allylic, and benzylic halides.

Nucleophile The nucleophile must be nonbasic to prevent a competitive elimination of HX but otherwise does not affect the reaction rate. Neutral nucleophileswork well.

Leaving group

Good leaving groups (more stable anions) increase the reaction rate by lowering the energy of the transition state leading to carbocation formation.

Solvents Polar solvents stabilize the carbocation intermediate by solvation, thereby increasing the reaction rate.


11.10 Elimination Reactions of Alkyl Halides: Zaitsev's Rule- most strong nucleophiles are also strong bases

Substitution

H

C

Br

CHO-

+ Br-

H

C

OH

C

- elimination reactions are more complicated than substitution: mixtures of alkenes

Elimination

H

C

Br

C C C H2O + Br-+

HO-


Zaitsev's rule In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates.

Br

NaOEt

EtOH+H3CHC CHCH3

81% 19%

Br

NaOEt

EtOH+H3CHC CCH3

70% 30%

CH3


11.11 The E2 Elimination Reactions; elimination, bimolecular

E2 elimination occurs when an alkyl halide treated with a strong base (HO-, RO-)

H

C

X

C C C

B+-H + X-+B:

H

C

X

C

Bδ+

δ-

E2 elimination: one step, concerted mechanism

Rate = k x [RX] x [Base]

Evidence for concerted mechanism: second-order kinetics, stereochemistries of products


E2 reaction occurs with a periplanar geometry; H-C-C-X are in the same plane; two periplanar geometries are possible

H

C

X

C

X

H

anti periplanar geometry(staggered, lower energy)

H

C

X

C

XH

syn periplanar geometry(eclipsed, higher energy)


anti periplanar reactant

H

X

anti periplanar TS

H

X

B

Overlap of the developing p orbitals in the transition state requires anti periplanar geometry of the reactant.


Similarity between SN2 and E2 mechanism

E2 reaction(anti periplanar)

XCNu

SN2 reaction(back-side attack)

CHC X

- an electron pair from nucleophile or C-H bond pushes the leaving group on the opposite site


H

C

PhBr Br

C

H Ph

Br

Ph HH

PhBr KOH

EtOH

HO-

BrPh

PhH

(Z)

- Antiperiplanar geometry for E2 elimination: the stereochemistry of an E2 elimination product depends on the stereochemistry the reactant


11.12 Elimination Reactions and Cyclohexane Conformation

H

Cl

H

HCl

H

Cl

H

base

E2+

axial chlorine: H and Cl are anti periplanar

Derek H. R. Barton, 1950; much of the chemical reactivity of substituted cycloalkanes is controlled by their conformation.

Conformation and reactivity


Conformation and reactivity

H

H

ClH

Hbase

E2

H

Cl

H

H

H

equatorial chlorine: H and Cl are not anti periplanar

No reaction fromthis conformation


Cl

NaOEt

EtOHfast

Neomenthyl chloride 78 : 22

+

Conformation and reactivity of cyclohexane

Cl

NaOEt

EtOH

slow

Menthyl chloride only


Cl

HH

NaOEt

trans diaxial

- consider most stable chair conformation first: i-Pr is equatorial- check antiperiplanar geometry: trans diaxial conformation is required for E2 elimination in cyclohexane systems

78 : 22

+

more substituted product formed as major


Conformation and reactivity of cyclohexane

Cl

NaOEt

EtOH

slow

Menthyl chloride only

200 times slower rate than neomenthyl chloride


H3C

ClH

HHring-flip

X

No reaction

no antiperiplanar HClCH3

H

only

:B

trans diaxial

CH3

H3C


11.13 The Deuterium Isotope Effect

CH

HCH2Br

baseCH CH2

CD

DCH2Br

baseCD CH2

Faster reaction

Slower reaction

Deuterium isotope effect: Because a C-H bond is weaker than a C-D bond by 5 kJ/mol (1.2 kcal/mol), a C-H bond is more easily broken than an equivalent C-D bond, and the rate of C-H bond cleavage is faster.


- support the one-step mechanism of E2 elimination

- the base-induced elimination of HBr is 7.11 times faster thancorresponding DBr elimination

; this result tells us that the C-H (or C-D) bond is broken in the rate limiting step.

; if it were otherwise, we couldn't measure a rate difference


11.14 The E1 Elimination; elimination, unimolecular

C

CH3

CH3

H3C Br

mechanism of E1 reaction

C

H2C

CH3

H3C

+ Br-

RDSH

base

fastC

CH2

CH3

H3C


- E1 and SN1 reactions normally occur in competition whenever an alkyl halide is treated in a protic solvent with a nonbasic nucleophile- the best E1 substrates are also the best SN1 substrates, and mixtures of substitution and elimination products are usually obtained.

C

CH3

CH3

H3C ClH2O

EtOH65oC

C

CH3

CH3

H3C OH C

CH2

CH3

H3C+

64 : 36


Rate = k x [RX]

Evidence for E1 mechanism- first-order kinetics

- no geometry requirement for E1 elimination - the more stable alkene is formed

- no deuterium isotope effect for E1 reaction: C-H bond cleavage is not the RDS


ClCH3

HH3C

ClH

HHring-flip

CH3

H3C H3C

1M NaOEtEtOH100oC

+

E2 conditions0.01M NaOEt80% aq.EtOH

160oCE1 conditions

100%68% 32%


11.15 Summary of Reactivity: SN1, SN2, E1, E2

There is no clear answers.

favored when bases are used

occurs in competition

with SN1no rxn

favored in hydrolytic

solventsR3CX

favored with strong base

can occur with benzylic and allylic halides

occurs in competition

with E2

can occur with benzylic and allylic halides

R2CHX

occurs with strong baseno rxn

highly favoredno rxnRCH2X

E2E1SN2SN1Halide type


• Primary alkyl halides: - SN2 substitution with good nucleophiles (RS-, I-, CN-, NH3, Br-)- E2 elimination with strong, hindered base (t-BuOK)

BrNaCN

THF-HMPA CN

BrKOt-Bu

90%

85%


• Secondary alkyl halides: SN2 and E2 compete- SN2 substitution: weakly basic nucleophiles in polar aprotic solvent- E2 elimination: strong base (EtO-, HO-, NH2-)

Br

NaOAc

(weak base)

OAc+

100 : 0

NaOEt

(strong base)

OEt+

20 : 80

- allylic, benzylic halides: SN1 and E1 can occur with weakly basic nucleophiles in protic solvents (EtOH, AcOH)


• Tertiary alkyl halides: - E2 elimination: base (RO-, HO-)- SN1 and E1: under neutral, hydrolytic condition

C

CH3

CH3

H3C Br

NaOEt

EtOHC

CH3

CH3

H3C OEt C

CH2

CH3

H3C+

3 : 97

EtOH

heatC

CH3

CH3

H3C OEt C

CH2

CH3

H3C+

80 : 20


Practice

Cl NaOMe

MeOH

Br

HCO2H

H2O

OCHO


11.16 Substitution Reactions in Synthesis

substitution reaction is the key bond forming reaction in organic synthesis

R NaR'CH2X

R CH2R' + NaX

X = Br, I, OTs

Examples studied

R Na R +

Br

7 : 93SN2 E2


Examples studied

C

CH3

CH3

H3C OH

+ Cl-

C

CH3

CH3

H3C

C

CH3

CH3

H3C Cl

+ OH2HCl

C

CH3

CH3

H3C OH

H

Cl-SN1

H3CH2C OHHCl

H3CH2C OH2

Cl-

H3CH2C Cl + H2O

SN2


RCH2 OHPBr3

RCH2HO

Br-SN2

PR'2 RCH2 Br

+P(OH)3

3 3

poor leaving groupgood leaving group

activation of alcohol

Methylation: the most common substitution reaction- in laboratory, use CH3-I- living organism use complex but safer methyl donor

Biological Substitution Reactions

Most biological reactions occur by the same addition, substitution, elimination, and rearrangement mechanisms encountered in laboratotyreactions.

Chemistry @ Work

- CH3Br: used as a fumigant to kill termites and as a soil sterilant; transfer an alkyl group to a nucleophilic amino group (-NH2) or mercapto group (-SH) in enzymes, thus altering the enzyme's normal biological activity.

many simple reactive SN2 substrates are toxic to living organisms


H

N

HOH OH

H HO

N

N

N

NH2

SCH3

HOOC

NH2

S-Adenosylmethionine

NH2

OHHO

HO

a sulfonium ion

Norepinephrine

SN2

H

N

HOH OH

H HO

N

N

N

NH2

SHOOC

NH2NH

OHHO

HO

CH3

+

Adrenaline

Chemistry @ Work


ClS

Cl

Mustard gas

ClS

internal

SN2Cl-

H2N ProteinSN2

HN Protein

SCl

Alkylated protein

mustard gas: chemical warfare agent, used in World War I

Chemistry @ Work

δ X δ electrophilic site C - Yonsei University€¦ · Ch.11 Nucleophilic Substitutions and...

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