organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd

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Chapter 3Mechanisms of Organic Reactions


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3.1Reaction Thermodynamics and Kinetics


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

Organic Reaction Mechanisms

Net Reaction and Mechanism

91

acid alcohol water

net reaction

reaction mechanism

starting materials products

elementary steps

catalyst

RO

OH+ HO R' R

O

O+

R'H 2 O

H

ROH

OH

H

HO R'

ROH

OHO

H

R'R

O

OHO

R'

HH

RO

OH

R'

+ H

H~+ H 2 O

ester


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Gibbs free reaction energyGR determines whether and in which direction the reaction runs standard Gibbs free reaction energyGR at standard conditions (1 bar, 25C, reactants 1 mol/L)

thermodyamics are concerned with the energy balance of chemical reactions

Thermodynamics of Chemical Reactions (1)

92

RO

OH+ HO R' R

O

O+

R'H 2 O

G R = G R + RT ln [RCOOR][H 2 O]

[RCOOH][ROH]

G R > 0

G R < 0

G R = 0

exergonic reaction, runs from left to right

endergonic reaction, runs from right to left

reaction is in equilibrium



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equilibrium constant KR is the ratio of reactant concentrations in equilibrium standard free reaction enthalpyGR determines the position of the equilibrium (at given temp.)



93

RO

OH+ HO R' R

O

O+

R'H 2 O

G R = G R + RT ln[RCOOR] eq [H2O]eq

[RCOOH] eq [ROH] eq= 0

K R =[RCOOR] eq [H2O]eq

[RCOOH] eq [ROH] eqpK R = log K R

G R = RT ln K R pK R G R RT



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standard reaction enthalpyHR is negative (advantageous) if bonds in products are stronger standard reaction entropySR is positive (advantageous) if the disorder increases



94

RO

OH+ HO R' R

O

O+

R'H 2 O

G R = H R T S R Gibbs-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 increase S R

> 0

S R < 0

H R > 0

H R < 0



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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 sid

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

Relation of Theromdynamics and Kinetics

A + B C + D r 2r = k 2r [C ][ D ]r 2f = k 2f [ A ][B ]

2f = 2r

k 2f [ A ][B ] = k 2r [C ][D ]

2f k 2r

=

[C ][D ]

[ A ][B ]= K



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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 pro

reaction proles are simplied energy diagrams of chemical reactions, following the lowestenergy path from the starting materials to the products in theenergy hypersurface

Reaction Proles (1)

P

S

E

dHBr

dHH

Br + H H H+Br H

S

E

Rkt

P



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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 pro

reaction proles are simplied energy diagrams of chemical reactions, following the lowestenergy path from the starting materials to the products in theenergy hypersurface

Reaction Proles (2)

P

S

E

dHBr

dHH

Br + H H H+Br H

S

E

Rkt

P



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Boltzmann distribution of molecular thermal energies

Relation of Reaction Proles, Thermodynamics, and Kinetics

S

E

Rkt

P

Gf = G

r < 0

Gf < G

r

S

E

Rkt

P

Gf = G

r > 0

Gf > G

r

K R =k f k r

exergonic reaction endergonic reaction

E A ,r G r

= RT ln k r E A , f G f

= RT ln k f

fastslow

slowfast

G R = G f

G r r f = r r k f [S] eq = k r [P] eqk f k r

=

[P] eq [S]eq

= K R



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Polanyi Principle:Diff erence in activation energies proportional to diff erence 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

Hammond Postulate and Polanyi Principle

1

2

3

S

E

Rkt

P1

P2

P3

G3f > G

2f = 0 > G

3f

G3f

> G2f

= G2r

> G3f

exergonic

endergonic

late transition statehigher activation energy

early transition statelower activation energy



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overall reaction rate and molecularity are controlled by slowest,rate-determining step typically, the generation of thereactive intermediateis 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 prole, i.e., betweenstarting materials (S), intermediates (I), and products (P), seprated by transition states ().

Multistep Reactions

101

1

I

E

Rkt

S

2

P

Gf = Gr < 0

G2f < G2r

elementary step 1 elementary step 2

slow fast

G1f > G1r



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change in standard Gibbs free reaction energyGRleads to change of equilibriumconcentrations

in reality, even more drastic because lnK ~ GR

Reaction Proles: Thermodynamics and Kinetics

102

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 ln K R

Rkt

S

E

P

Gf = G

r < 0



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change in Gibbs free energy of transition stateG leads to change in reaction rates in reality, even more drastic because lnk ~ G


103

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

G f = RT ln k f G

r

= RT ln k r and



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104

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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change in temperature changes equilbrium (due to Gibbs-Helmholtz equationG =H TS) change in temperature also causes reaction rates because of thermal energy of molecules


105

lower temperature higher temperatureforward/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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3.2Classication of Organic Reactions

Cl i i f O i i (1)


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classication according toreaction type, i.e., the type of changes to molecular topology

Classication of Organic Reactions (1)

107

R 1X R 2

R 3

+ YR 1

YR 2R 3

+XSubstitution

Substitution

R 3R 1

R 2 R 4

Y

X

R 2 R 3R 4

R 1+ X + Y

Addition

Elimination

R3R 1

R 2 R4

+ YY

R 2R 3R 4

R 1

Addition

Elimination

R 1X

Y R3

R 2X

Y R3

R 2

R 1

Rearrangement

Rearrangement


Cl i i f O i R i (2)


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classication according toreactive intermediate

Classication of Organic Reactions (2)

108

RR

R

H

H

R1C

R 2R 3

RR

R

X

X

RR

R

Y

Y

R 1C

R 2

R 3

CR 1R 2

R3

carbanionsp3

pyramidal

carbocationsp2

planar

carbon radicalsp2 or sp2 or in between

planar or pyramidal

bond heterolysis bond homolysis

polar mechanismsnucleophiles or electrophiles

radical mechanismsradical starters



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3.3Nucleophilic Substitutions (SN Reactions)

N l hili S b tit ti (SR ti )


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

Nucleophilic Substitutions (SN Reactions)

110

R1C LG

R 2 R 3

+Nu

R 1CNu

R 2R 3

+ LG

R1

R 2R3

R1

R 2R3

Nu LG

NuLG +

nucleophilic substitutionnucleophile leaving group

electrophilic center

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

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

transition state

intermediate


S 1 M h i R t D t i i g St i U i l l


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the departure of the leaving group generates a carbocation 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 (favorabl

SN1 Mechanism: Rate-Determining Step is Unimolecular

111

R1C LG

R2 R3

R1CNu

R2R3

+R1

R2R3

sp 3 sp 3sp 2

LG

Nu+

R1C Nu

R2 R3

sp 3

or1

I

E

Rkt

S

2

P

Gf = G

r < 0

G2f

< G2r

slow fast

G1f

> G1r

racemic mixturepure enantiomer planar, achiral


E l f S1 R ti


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Examples of SN1 Reactions

112

Cl + MeOH Cl + MeOH O

Me

H H OMe

trityl chloride methanol

good leaving group

excellently stabilized cation

moderate nucleophile

OTf +O

O

CH 3NaOAc

TfO CH 2

Br Br

+

Na

OAc

Br

Na

benzylbromotriate sodium acetate

excellent leaving group

well-stabilized cation

moderate nucleophile


Analogy of S1 Reactions and Acid Base Reactions


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pKAvalues are a measure of the strength of a Brnsted acid the lower the pKA value, the more is the equilibrium on the side of the dissociated ions pKA values of the corresponding acids are a measure for leaving group quality (lower is better

SN1 reactions are cation-anion dissociation reactions like acid-base reactions

Analogy of SN1 Reactions and Acid-Base Reactions

113

pK A = log K A = log [H+ ][LG ]

HLG


RLGR

R

+ LGR

RR

H LG + LGH

SN1 reaction

acid-base reaction

Brsted acid

Brsted acid leaving group

conjugate base

Leaving Group Quality


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residues that correspond to acids withpKA < 0aregood leaving groups residues that correspond to acids withpKA < 10 aremoderate leaving groups residues that correspond to acids withpKA < 20 arepoor leaving groups residues that correspond to acids withpKA > 20 arenot leaving groups at all

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

Leaving Group Quality

114

OH

5

O

Me>OH

1

O

CF 3>OH

10

SO

Me>

15

O

OH SO

CF 3

O

>OH

7

SO O

FHClHBrHIH >>>

10 9 7 3

FH OHH NH 2H CH 3H> > >

3 16 38 48


Trivial Names and Abbreviations of Important Leaving Groups


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Trivial Names and Abbreviations of Important Leaving Groups

115

OR

O

Me>OR

O

CF 3>OR SO

Me>

O

OR SO

CF 3

O

>OR SO O

OAcROTFAROMsROTf R OTsR

triuoromethanesulfonatetriate

methanesulfonatemesylate

4-toluenesulfonatetosylate

triuoroacetate acetate


Stabilization of the Carbocation Intermediate (1)


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

carbocationsare electron-decient, must be stabilized by electron-donating groups


116

triphenylmethyltrityl

diphenylmethyl

phenylmethylbenzyl

ethenylmethylallyl

tertiarycarbon

secondarycarbon

primarycarbon

phenyl(sp2)


H

H

H

R R

R

R R

H

R H

H> > > > >

R Si

R

R

>>> CH

H>> >

>>

RSn

R

R

>>

>

H

H

D

H

H>

A



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

stabilization by resonance (+M eff ect)


117

H

H

H

C

H

H

HC

H

H

CH

H

H

H

H

compare to phenyl cation

H

HHC

H

H

C

H

H

H

H

RO RO RO RO CH

H

H

RO




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the more alkyl groups (the higher substituted), the better stabilized is carbocation

stabilization by inductive eff ects (+I eff ect); conceptual explanation by hyperconjugation


118

R Sn

R

R

R Si

R

R

R C

R

R> >

C C

H

H

H!

! +

R3 N

R2 S > R2 O

>

>

R3 C > R2 N RO > F>> >>

I > Br Cl > F>

C O

RR

R

>C O

HR

R

>C O

HR

H

>C O

HH

H

Pearson et al., J. Am. Chem. Soc.1968 , 90, 3319.

Examples for Nucleophilic Substitutions


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Examples for Nucleophilic Substitutions

121

Br

Br

EtO OEt

Br

+

OMe

Br

EtO OMe

EtO

+

Br

Br

EtO Br

EtO

+

OTf Cl

EtO+OEt

Cl

Br

Br

Br

TfO

Si Cl

Cl

EtO+

Si OEt

ClCl


Nucleophilic Reactions on Carbonyl Compounds


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aldehydes (H) and ketones (R) haveno leaving groups amides (NR2), acids (OH), and carboxylates havevery poor leaving groups acid halides, anhydrides (and some esters) havegood (or at least moderate) leaving groups reminder:leaving group quality strictly controlled by basicity of the leaving group anion!

carbonyl carbon atoms are inherently very reactive electrophilic centers

Nucleophilic Reactions on Carbonyl Compounds

122

R C R

O

R C R

O R

RO

R

RO

(HOMO) * (LUMO)

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

acid halides acid anhydrides ketones aldehydes esters amides acids carboxylate

electrophilicity controlled by M eff ect and I eff ect


Nucleophilic Substitution on Carbonyl Compounds: AdditionElimination Mechanism (SAE)


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

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

Nucleophilic Substitution on Carbonyl Compounds: Addition Elimination Mechanism (SAE)

123

OC

Nu LGR+

sp2

sp3

CO

LGR

Nu+

or

OC

NuLGR

sp3

LG

sp2

CO

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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a p es o uc eop c Subst tut o s o Ca bo y Ca bo s

125

OH

Cl S

O O

CH 3

NEt 3

HNEt 3 Cl

O TsClS

OO

CH 3

OTs

NH 2

NEt 3

HNEt 3 AcO

HNAc 2 O NHAc

O

O

H 3 C

O

CH 3CH 3

OOH HO OH

tosylation

acetylation


Example: Peptide Coupling Reactions


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solution: peptide coupling reagents

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

p p p g

126

dicyclohexylcarbodiimide(DCC)

R

O

OH

+ H 2 N R'

R

O

O

+ H 3 N R'

R

O

O H

NC

N

NEt 3

H NEt 3R

OO

N HC

N

O

O

R

+ H NEt 3NEt 3

H 2 N R'

NH

O

R R' +

NH

CNH

O

peptide



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3.4Electrophilic Additions to Olens (AE Reactions)

Reactions of Olens with Electrophiles


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p

128

R REl El

H

H

H

H

H H

Nu+ REl

H

H HNu

R R COOH Cl> > >

R

PhR

RR

R

R

ROR >>>>

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

reactivity order

decreasing electron density (M or I eff ect)


Examples


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p

129

hydrohalogenation of olens

hydration of olensH

OH

H HSO 4

H 2 O

H

BrH Br

Br

BrBr Br

halogen addition to olens



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Regioselectivity of Electrophilic Additions: Markovnikov-Rule


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131

1

I

E

Rkt

S

2

P

Gf < G

r

G2f

< G2r

slow

fast

G1

> G1

1

I

P

2

G2f

< G2r

slowerfast

H

HH

H

H

H

Ph

Br

Br

H

Ph

H

H

HPh

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 yo

have, the more you get)



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3.5Electrophilic Substitutions on Aromatic Compounds

Multiple Bonds Aromatic Compounds Do Not React Like Olens


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134

ElEl

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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135

bromination

Friedl-Crafts alkylation and acylation

sulfonation and nitration

H Br+ AlBrCl 3

R R

H ClR R

O O

Br AlCl 3

! ! +

R

Cl AlCl 3! ! +

R

O

+ AlCl 3

+ AlCl 3

+ AlCl 4

H BrBr Br

+ FeCl 3

Br Br FeCl 3

! ! +

+ FeBrCl 3

H SO 3 HH 2 SO 4

H2

O

H NO 2HNO 3 / H 2 SO 4

H 2 ONO 2 H 3 O 2 HSO 4

HSO 3 HSO 4


Mechanism of Electrophilic Aromatic Substitutions


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136

complex

addition product

substitution product

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

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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137

substituents with +M eff ect direct the electrophile intoortho or para-positions substituents with +M eff ect increase electron density, nucleophilicity, reactivity

RO

HC

RO

CH

HCRORO

RO

RHN>

RO>

I>

Br>

Cl>

F>

paramajor

metanone

orthominor

BrBr Br

+ FeCl 3RO RO

+

RO

+

ROBr

Br


Regioselectivity in Electrophilic Aromatic Substitutions


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138

substituents with M eff ect direct the electrophile intometa-positions substituents with M eff ect decrease electron density, nucleophilicity, reactivity

HC CH

HC

O

RO

O

RO

O

RO

O

ROO

RO

para

traces

meta

major

ortho

traces

BrBr Br

+ FeCl 3O 2 N O 2 N

+

O 2 N

+

O 2 NBrBr

S>

N> > > >>

O

RO

O O

O

O

RO

O

RN

O

HO

O

O

H

sulfonate nitro carboxylic esters carboxylic amides carboxylic acids carboxylat



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3.6Elimination Reactions

-Hydrogen Eliminations


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140

most common are eliminations of hydrogen (H) and leaving group (LG) on adjacent carbonsE1 mechanism:leaving group leavesrst, hydrogen leaves subsequently

E1cb mechanism:baserst removes hydrogen and generates conjugate base, then leaving group le

E2 mechanism:concerted reaction

-hydrogen eliminations are reverse reactions of electrophilic additions to olens

olen

LG

CR

4R 3

C R 1

R2

CR3H

CH R 1

R 2H H

C C R 1

H R 2

HR 3 LG

+ Base

H BaseC C R 1

R 2

HR3

LG

C C R 1

H R 2

HR 3

LG

Base !

! +

! +!

!

"#

LG


Competition of SN1 and E1 Reactions


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141

E1 eliminations are inevitable side reactions of SN

1-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

LGCR3

HCH R1

R2

H

C C R1H R2

HR3 LG

H

Nu+

CR4R3 C R1R

2

C C R2

H

R1HR3

Nu

C C R1

H R2

HR3 Nu+

(base)

E1 Elimination

SN1 Substitution


Competition of SN2 and E1cb /E2 Reactions


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142Organic Reaction Mechanisms

eliminations are often-observed side reactions of SN

2-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 R 1H R 2

HR 3

LG

+ Base

H BaseC C R 1

R 2

HR 3

LGC

R4R 3

C R 1

R2

Nu+

C CR 1

HR 2

HR3

LG

Nu

C CR 2

H

R 1HR3

Nu

LG

Non-Nucleophilic Bases


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143Organic Reaction Mechanisms

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

lithium diisopropylamideLDA, pKA 40 lithium hexamethyldisilazideLHMDS, pKA 40

diisopropylethylamineDIEA, pKA 10

triisopropylamineTIPA, pKA 10

1,8-bis(dimethylamino)naphthaleneproton sponge, pKA 12

1,4-diazabicyclo[2.2.2]octaneDABCO, pKA 12 1,5-diazabicyclo[4.3.0]non-5-eneDBN, pKA 12 1,8-Diazabicyclo[5.4.0]undec-7-eneDBU, pKA 12

N

Li

SiN

Si

Li

N

N

N

N

N

N

N N

N N


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3.7Radical Substitutions and Additions

Radical Substitution Reactions (SR)


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145

initiation

CH 3

Cl Cl 2 Cl

+ Cl CH 2 + H Cl

CH 2 + Cl Cl CH 2 Cl + Cl

2 Cl Cl Cl

CH 2 + Cl CH 2 Cl

CH 22 CH 2 CH 2

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

2 CH CH

Br

HC Br + Br

Br

Br

Br

BrHC Br

HC Br

BrH 2 C CH 2 Br

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