Organic Chemistry 3

7/28/2019 Organic Chemistry 3

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Chapter 3

Mechanisms of Organic Reactions


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3.1

Reaction Thermodynamics nd Kinetics


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Organic Reaction Mechanisms

Net Reaction and Mechanism

91

acid alcohol water

net reaction

reaction mechanism

starting materials products

elementary steps

catalyst

net reactiondescribes the starting materials and the products of a reaction reaction mechanismsdescribes the individual elementary steps of the reaction catalyst takes part in the reaction mechanism but is retained unchanged

R

O

OH

+ HO R' R

O

O

+

R'

H2O

H

R

OH

OH

H

HO R'

R

OH

OH

O

H

R'

R

O

OH

O

R'

H

H

R

O

OH

R'

+ H

H~+ H2O

ester


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Thermodynamics of Chemical Reactions (1)

92

R

O

OH

+ HO R' R

O

O

+

R'

H2O

GR=G

R+RT ln

[RCOOR][H2O]

[RCOOH][ROH]

GR> 0

GR< 0

GR= 0

exergonic reaction, runs from left to right

endergonic reaction, runs from right to left

reaction is in equilibrium

Gibbs free reaction energy GRdetermines whether and in which direction the reaction runs standard Gibbs free reaction energy GRat standard conditions (1 bar, 25C, reactants 1 mol/L)

thermodyamicsare concerned with the energy balance of chemical reactions



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93

R

O

OH

+ HO R' R

O

O

+

R'

H2O

equilibrium constant KRis the ratio of reactant concentrations in equilibrium standard free reaction enthalpy GRdetermines the position of the equilibrium (at given temp.)


GR=G

R+RT ln

[RCOOR]eq[H2O]eq

[RCOOH]eq[ROH]eq= 0

KR=[RCOOR ]eq[H2O]eq

[RCOOH]eq[ROH]eqpKR= logKR

G

R=RT lnKR pKR

GR

RT



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94

R

O

OH

+ HO R' R

O

O

+

R'

H2O

standard reaction enthalpy HRis negative (advantageous) if bonds in products are stronger standard reaction entropy SRis positive (advantageous) if the disorder increases


G

R=H

RTS

RGibbs-Helmholtz Equation

exothermic reactions, sum of all bond energy changes negative

endothermic reactions, sum of all bond energy changes positive

exotropic reactions, disorder, degrees of freedom decrease

endotropic reactions, disorder, degrees of freedom increaseSR> 0

S

R< 0

H

R> 0

H

R< 0



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Kinetics of Chemical Reactions

95

reaction rates rare proportional to the product of the concentrations of all reactants

rate constants kare the proportionality factors reaction order is the sum of all exponents of the concentrations of all reactants in the rate law molecularityis the number of molecules actually involved in an elementary reaction for simple, single-step reactions, the molecularity determines the reaction order

reaction kinetics refers to how fast reactions proceed, i.e., the reaction rates rate lawsdescribe the relation between substrate concentrations and reaction rates

A B

A + B C + D

A + B + C D

r1r = k1r [B]r1f= k1f [A]

r2r= k2r [C][D]r2f= k2f [A][B]

r3f= k3f [A][B][C]

r4f= k4f [A]2[C]

r3r = k3r [D]

rst order monomolecular monomolecular rst order

second order bimolecular bimolecular second order

third order trimolecular monomolecular rst order

third order trimolecular bimolecular second order

r4r = k4r [C]2 A + B 2 C



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Relation of Theromdynamics and Kinetics

96

the ratio of rate constants of forward and reverse reactions determines equilbrium constant K the faster the forward reaction (relative to reverse), the larger is K the faster the forward (relative to reverse) reaction, the more the equilibrium is on product side

in thermodyamic equilibrium, concentrations of reactants do not change anymore forward and reverse reaction are equally fast


A + B C + D r2r= k2r [C][D]r2f= k2f [A][B]

r2f= r2r

k2f [A][B]= k2r [C][D]

k2f

k2r=

[C][D]

[A][B]=K


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Reaction Profiles (1)

97

P

S

E

dHBr

dHH

Br + H H H+Br H

S

E

Rkt

P

reaction profilesare simplified energy diagrams of chemical reactions, following the lowestenergy path from the starting materials to the products in the energy hypersurface

starting materials (S) and products (P) are stable compounds, i.e., energetic minima transition states () are saddle points in the energy hypersurface, maxima in the reaction profile



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Reaction Profiles (2)

98

P

S

E

dHBr

dHH

Br + H H H+Br H

S

E

Rkt

P

reaction profilesare simplified energy diagrams of chemical reactions, following the lowestenergy path from the starting materials to the products in the energy hypersurface

starting materials (S) and products (P) are stable compounds, i.e., energetic minima transition states () are saddle points in the energy hypersurface, maxima in the reaction profile



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Relation of Reaction Profiles, Thermodynamics, and Kinetics

99

S

E

Rkt

P

Gf

= Gr

< 0

Gf

< Gr

S

E

Rkt

P

Gf

= Gr

> 0

Gf

> Gr

KR=f

kr

Boltzmann distribution of molecular thermal energies

exergonic reaction endergonic reaction

EA,r Gr=RT lnkrEA,fG

f=RT lnkf

fast

slow

slow

fast

GR=G

fGr f= r kf[S]eq =kr [P]eq

f

kr=

[P]eq

[S]eq=KR



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Hammond Postulate and Polanyi Principle

100

1

2

3

S

E

Rkt

P1

P2

P3

G3f

> G2f

= 0 >G3f

G3f

> G2f

= G2r

>G3f

Polanyi Principle: Difference in activation energies proportional to difference in free enthalpies Hammond Postulate: Energetically more similar states are also geometrically more similar

Polanyi Principle and Hammond Postulate for mechanistically similar, single-step reactions

exergonic

endergonic

late transition state

higher activation energy

early transition state

lower activation energy



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Multistep Reactions

101

1

I

E

Rkt

S

2

P

Gf = G

r < 0

G2f

< G2r

elementary step 1 elementary step 2

slow fast

G1f

> G1r

overall reaction rate and molecularity are controlled by slowest, rate-determining step typically, the generation of the reactive intermediate is the rate-determining step intermediate is a good approximation for the transition state of the rate-determining step

elementary reactions are steps between the minima in the reaction profile, i.e., between startingmaterials (S), intermediates (I), and products (P), seprated by transition states ().



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Reaction Profiles: Thermodynamics and Kinetics

102

change in standard Gibbs free reaction energy GR leads to change of equilibrium concentrations in reality, even more drastic because ln K~ GR


S

E

Rkt

P

Gf = G

r < 0

less exergonic reaction more exergonic reaction

equilibrium less on product side equilibrium more on product side

G

R=RT lnKR

Rkt

S

E

P

Gf = G

r < 0


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103

change in Gibbs free energy of transition state G leads to change in reaction rates in reality, even more drastic because ln k~ G


higher energy transition state lower energy transition state

forward/reverse reactions slower forward/reverse reactions faster

S

E

Rkt

P

Gf = G

r < 0

Gf

Gr

S

E

Rkt

P

Gf = G

r < 0

Gf

Gr

Gf=RT lnkf G

r=RT lnkrand


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104Organic Reaction Mechanisms

higher energy transition state very high energy transition state

forward/reverse reactions slower

S

E

Rkt

P

Gf = G

r < 0

Gf

Gr

equilibrium cannot be established

metastable

S

E

Rkt

P

Gf = G

r < 0

Gf

Gr


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105

change in temperature changes equilbrium (due to Gibbs-Helmholtz equation G = H T S) change in temperature also causes reaction rates because of thermal energy of molecules


lower temperature higher temperature

forward/reverse reactions slower forward/reverse reactions faster

S

E

Rkt

P

Gf = G

r < 0

Gf

Gr

Rkt

S

E

P

Gf = G

r < 0

for endotropic reaction (S>0):equilbrium less on the product side

for endotropic reaction (S>0):equilbrium more on the product side


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3.2

Classication of Organic Reactions


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Classification of Organic Reactions (1)

107

classification according to reaction type, i.e., the type of changes to molecular topology

R1X R2

R3

+ Y

R1YR2

R3

+X

Substitution

Substitution

R3R1

R2 R4

Y

X

R2R3R4

R1+ X + Y

Addition

Elimination

R3R1

R2 R4

+ Y

Y

R2R3R4

R1

Addition

Elimination

R1XYR3

R2

XYR3

R2

R1

Rearrangement

Rearrangement



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Classification of Organic Reactions (2)

108

classification according to reactive intermediate


RRR

H

H

R1

C

R2

R3

RRR

X

X

RRR

Y

Y

R1C

R2

R3

CR1R2

R3

carbanionsp3

pyramidal

carbocationsp2

planar

carbon radicalsp2 or sp2 or in between

planar or pyramidal

bond heterolysis bond homolysis

polar mechanisms

nucleophiles or electrophiles

radical mechanisms

radical starters


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3.3

Nucleophilic Substitutions (SN Reactions)


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Nucleophilic Substitutions (SN Reactions)


R1

C LG

R2 R3

+Nu

R1

CNu

R2R3

+ LG

R1

R2R3

R1

R2R3

Nu LG

NuLG +

nucleophilic substitution

nucleophile leaving group

electrophilic center

SN1 Mechanism: leaving group leaves rst (and allows nucleophile to come in subsequently

SN2 Mechanism: nucleophile attacks (and forces leaving group to leave simultaneously)

transition state

intermediate

a nucleophile is an electron pair donor, an electrophile is an electron pair acceptor


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SN1 Mechanism: Rate-Determining Step is Unimolecular

111

R1C LG

R2R3

R1CNu

R2R3

+

R1

R2R3

sp3 sp3sp2

LG

Nu+

R1C Nu

R2R3

sp3

or

1

I

E

Rkt

S

2

P

Gf = G

r < 0

G2f

< G2r

slow fast

G1f

> G1r


the departure of the leaving group generates a carbokation as a true intermediate the formation of the intermediate is energetically disfavorable, rate-determining good leaving group, stabilized carbocation will decrease energy of the intermediate (favorable)

racemic mixturepure enantiomer planar, achiral


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Leaving Group Quality

112

leaving group quality is approximately inverse to the basicity of the obtained anion scale by pKA values of the corresponding acids

OH

5

O

Me>OH

1

O

CF3>OH

10

SO

Me>

15

O

OHS

O

CF3

O

>OH

7

SO O

FHClHBrHIH >>>

10 9 7 3

FH OHH NH2H CH3H> > >

3 16 38 48

residues with corresponding pKA < 0 are good leaving groups

residues with corresponding pKA < 10 are moderate leaving groups residues with corresponding pKA < 20 are poor leaving groups residues with corresponding pKA > 20 are not leaving groups at all


pKA= logKA= log[H+][LG]

HLG


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Trivial Names and Abbreviations of Important Leaving Groups

113

OR

O

Me>OR

O

CF3>ORS

O

Me>

O

ORS

O

CF3

O

>ORS

O O

OAcROTFAROMsROTfR OTsR

triuoromethanesulfonatetriate

methanesulfonatemesylate

4-toluenesulfonatetosylate

triuoroacetate acetate



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Stabilization of the Carbocation Intermediate (1)


carbocations are electron-deficient, must be stabilized by electron-donating groups

H

H

H

R R

R

R R

H

R H

H

> > > > >

RSi

R

R

>>> CH

H

>> >

>>

RSn

R

R

>>

SN1 reactions very favorable in benzyl or allyl position SN1 reactions also observed on highly substituted sp3 carbons SN1 reactions never observed in phenyl position (or other sp2 or sp carbons)

triphenylmethyltrityl

diphenylmethyl phenylmethylbenzyl

ethenylmethylallyl

tertiarycarbon

secondarycarbon

primarycarbon

phenyl(sp2)


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H

H

H

C

H

H

HC

H

H

CH

H

H

H

H

stabilization by resonance (+M effect)

compare to phenyl cation

H

H

HC

H

H

C

H

H

H

H

RO RO RO ROCH

H

H

RO

the more delocalization (donor groups, larger aromatic systems), the better stabilization


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stabilization by inductive effects (+I effect); conceptual explanation by hyperconjugation

RSn

R

R

RSi

R

R

RC

R

R

> >

C C

H

H

H!

!+

R3N

R2S> R2O

>

>

R3C> R2N RO > F>> >>

I > Br Cl > F>

C OR

R

R

>C OH

R

R

>C OH

R

H

>C OH

H

H

E l f N l hili S b i i


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Examples for Nucleophilic Substitutions

120

Br

Br

EtO OEt

Br

+

OMe

Br

EtO OMe

EtO

+

Br

Br

EtO Br

EtO

+

OTfCl

EtO+OEt

Cl

Br

Br

Br

TfO

SiCl

Cl

EtO+

SiOEt

ClCl

N l hili R ti C b l C d


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Nucleophilic Reactions on Carbonyl Compounds

121

RCR

O

RCR

O R

RO

R

RO

carbonyl carbon atoms are inherently very reactive electrophilic centers

(HOMO) * (LUMO)

electrophilicity controlled by M effect and I effect

R H

O

R OR'

O

> > >R R'

O

R OH

O

R O

O

> >R' NR'2

O

R O

O

> >R Hal

O O

R

aldehydes (H) and ketones (R) have no leaving groups

amides (NR2), acids (OH), and carboxylates have very poor leaving groups acid halides, anhydrides (and some esters) have good (or at least moderate) leaving groups reminder: leaving group quality strictly controlled by basicity of the leaving group anion!

acid halides acid anhydrides ketones aldehydes esters amides acids carboxylates


N l hili S b tit ti C b l C d Additi Eli i ti M h i (S )


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Nucleophilic Substitution on Carbonyl Compounds: AdditionElimination Mechanism (SAE)

122

carbonyl carbons are very reactive electrophilic centers carbonyl carbons are sp2 hybridized, coordinatively unsaturated

addition of the nucleophile prior to cleavage of the leaving group is possible, advantageous!

O

CNu LG

R

+

sp2 sp3

C

O

LGR

Nu+

or

O

CNuLG

R

sp3

LG

sp2

C

O

LGR

Nu+

1

I

E

Rkt

S

2

P

Gf = G

r < 0

G2f

< G2r

slow fast

G1f

> G1r



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Examples for Nucleophilic Substitutions on Carbonyl Carbons


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Examples for Nucleophilic Substitutions on Carbonyl Carbons

124

OH

ClS

O O

CH3

NEt3

HNEt3 Cl

OTsClS

O

O

CH3

OTs

NH2

NEt3

HNEt3 AcO

HNAc2ONHAc

O

O

H3C

O

CH3

CH3

OOH HO OH

tosylation

acetylation


Example: Peptide Coupling Reactions


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Example: Peptide Coupling Reactions

125

no amide (peptide) formation between carboxylic acid and amine:

solution: peptide coupling reagents dicyclohexylcarbodiimide (DCC)

R

O

OH

+ H2

N R'

R

O

O

+ H3

N R'

R

O

OH

NCN

NEt3

HNEt3R

O

O

NHC

N

O

O

R

+ HNEt3

NEt3

H2N R'

N

H

O

RR' +

N

H

CN

H

O

peptide



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3.4

Electrophilic Additions to Olens (AE Reactions)

Reactions of Olefins with Electrophiles


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Reactions of Olefins with Electrophiles

127

R R

ElEl

H

H

H

H

H H

Nu+ REl

H

H HNu

R R COOH Cl> > >

R

PhR

R

R

R

R

ROR >>>>

olefins are (weak) nucleophiles and react with electrophiles to form carbocations

reactivity order

decreasing electron density (M or I effect)



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41/57

Regioselectivity of Electrophilic Additions: Markovnikov-Rule


42/57

Regioselectivity of Electrophilic Additions: Markovnikov-Rule

130

1

I

E

Rkt

S

2

P

Gf < G

r

G2f

< G2r

slow

fast

G1

> G1

1

I

P

2

G2f

< G2r

slowerfast

H

H

H

H

H

H

Ph

Br

Br

H

Ph

H

H

H

Ph

H

H Br

H

H

Ph

H

H

Br

Br

H

H

H

Ph

H

electrophile adds to double bond so that more stable cation is formed IMarkovnikov rule: in HX addition, X is added to the higher substituted carbon (the more you

have, the more you get)



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3.5

Electrophilic Substitutions on Aromatic Compounds

Multiple Bonds Aromatic Compounds Do Not React Like Olefins


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Multiple Bonds Aromatic Compounds Do Not React Like Olefins

133

El

El

H

H

H

Nu+

H

H

El

El

HH

Nu

H

Elelctrophilic Addition

Elelctrophilic Substitution

electrophilic addition leads to loss of aromaticity, energetically disfavorable electrophilic Substitution re-establishes aromatic system


Examples


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Examples

134

bromination

Friedl-Crafts alkylation and acylation

sulfonation and nitration

H Br+ AlBrCl3

R R

H ClR R

O O

Br AlCl3

!!+

R

Cl AlCl3

!!+

R

O

+ AlCl3

+ AlCl3

+ AlCl4

H BrBr Br

+ FeCl3

Br Br FeCl3

!!+

+ FeBrCl3

H SO3HH2SO4

H2O

H NO2HNO3 / H2SO4

H2O

NO2 H3O 2 HSO4

HSO3 HSO4


Mechanism of Electrophilic Aromatic Substitutions


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Mechanism of Electrophilic Aromatic Substitutions

135

complex

addition product

substitution product

in electrophilic aromatic substituions, the most acidic hydrogen is replaced with an electrophile

1

E

Rkt

S

2

P

P

Gf = G

r < 0

G2f

< G2r

slow fast

G1f

> G1r

0

ElH

H

ElHEl

HH

H

El

complex


Regioselectivity in Electrophilic Aromatic Substitutions


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136

substituents with +M effect direct the electrophile into ortho orpara-positions substituents with +M effect increase electron density, nucleophilicity, reactivity

RO

HC

RO

CH

HCRORO

RO

RHN

>

RO

>

I

>

Br

>

Cl

>

F

>

para

major

meta

none

ortho

minor

BrBr Br

+ FeCl3RO RO

+

RO

+

ROBr

Br




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137

substituents with M effect direct the electrophile into meta-positions substituents with M effect decrease electron density, nucleophilicity, reactivity

HC CH

HC

O

RO

O

RO

O

RO

O

RO

O

RO

para

traces

meta

major

ortho

traces

BrBr Br

+ FeCl3O2N O2N

+

O2N

+

O2NBr

Br

S

>

N

> > > >>

O

RO

O O

O

O

RO

O

RN

O

HO

O

O

H

sulfonate nitro carboxylic esters carboxylic amides carboxylic acids carboxylates



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3.6

Elimination Reactions

-Hydrogen Eliminations


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y g

139

most common are eliminations of hydrogen (H) and leaving group (LG) on adjacent carbons

E1 mechanism: leaving group leaves rst, hydrogen leaves subsequently

E1cb mechanism: base rst removes hydrogen and generates conjugate base, then leaving group leaves

E2 mechanism: concerted reaction

-hydrogen eliminations are reverse reactions of electrophilic additions to olefins

olen

LG

CR

4R3

C R1

R2

CR3

H

CH R1

R2

H H

C C R1

H R2

HR3

LG

+ Base

H Base

C C R1

R2

H

R3LG

C C R1

H R2

H

R3LG

Base!

!+

!+!

!

"#

LG


Competition of SN1 and E1 Reactions


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p N

140

E1 eliminations are inevitable side reactions of SN1-type substitution reactions! Factors:

both: good leaving group, stabilized carbocation (identical intermediate!) E1: absence of a nucleophile, non-nucleophilic base (if any), many or acidic-hydrogens SN1: presence of a (good, not too basic) nucleophile, few or non-acidic -hydrogens

LG

CR3H

CH R1

R2

H

C C R1H R2

HR3

LG

H

Nu+

CR4R3

CR1

R2

C C R2

H

R1HR3

NuC C R1

H R2

HR3 Nu

+

(base)

E1 Elimination

SN1 Substitution


Competition of SN2 and E1cb/E2 Reactions


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p


eliminations are often-observed side reactions of SN2-type substitution reactions!

however, they do not share the same intermediate E1cb/E2: moderate/poor leaving group, strong non-nucleophilic base, acidic -hydrogens SN2: good, non-basic nucleophile (e.g., I, RS, PR3, H2O), few or non-acidic -hydrogens

E1cb Elimination

SN2 Substitution

C C R1

H R2

H

R3LG

+ Base

H BaseC C R1

R2

HR3

LG

CR4R3

CR1

R2

Nu+

C CR1

HR2

HR3

LG

Nu

C CR2

H

R1HR3

Nu

LG

Non-Nucleophilic Bases


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p


non-nucleophilic bases have a high pKA (of BH) but are strongly sterically hindered!

lithium diisopropylamideLDA, pKA 40

lithium hexamethyldisilazideLHMDS, pKA 40

diisopropylethylamine

DIEA, pKA 10

triisopropylamine

TIPA, pKA 10

1,8-bis(dimethylamino)naphthalene

proton sponge, pKA 12

1,4-diazabicyclo[2.2.2]octane

DABCO, pKA 12

1,5-diazabicyclo[4.3.0]non-5-ene

DBN, pKA 12

1,8-Diazabicyclo[5.4.0]undec-7-ene

DBU, pKA 12

N

Li

SiN

Si

Li

N

N

N

N

N

N

N N

N N


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3.7

Radical Substitutions and Additions

Radical Substitution Reactions (SR)


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144

initiation

CH3

Cl Cl 2 Cl

+ ClCH2 + H Cl

CH2 + Cl ClCH2Cl + Cl

2 Cl Cl Cl

CH2 + ClCH2Cl

CH22CH2 CH2

propagation

termination reactions

product

side product

product


Radical Addition Reactions (AR)


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initiation

propagation

termination reactions

product

side product

product

Br Br 2 Br

+ Br

HC

+ Br Br

2 Br Br Br

+ Br

2CH CH

Br

HC Br

+ Br

Br

Br

Br

BrHC Br

HC Br

BrH2C CH2Br

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Organic Chemistry 3