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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
Organic Reaction Mechanisms
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Thermodynamics of Chemical Reactions (2)
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.)
thermodyamicsare concerned with the energy balance of chemical reactions
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
Organic Reaction Mechanisms
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Thermodynamics of Chemical Reactions (3)
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
thermodyamicsare concerned with the energy balance of chemical reactions
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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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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 ().
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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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Reaction Profiles: Thermodynamics and Kinetics
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
Organic Reaction Mechanisms
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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Reaction Profiles: Thermodynamics and Kinetics
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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Reaction Profiles: Thermodynamics and Kinetics
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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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Classification of Organic Reactions (2)
108
classification according to reactive intermediate
Organic Reaction Mechanisms
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)
110Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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Stabilization of the Carbocation Intermediate (1)
114Organic Reaction Mechanisms
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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Stabilization of the Carbocation Intermediate (2)
115Organic Reaction Mechanisms
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 of the Carbocation Intermediate (3)
116Organic Reaction Mechanisms
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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Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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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)
Organic Reaction Mechanisms
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Regioselectivity of Electrophilic Additions: Markovnikov-Rule
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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)
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
Regioselectivity in Electrophilic Aromatic Substitutions
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Regioselectivity in Electrophilic Aromatic Substitutions
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
Organic Reaction Mechanisms
Regioselectivity in Electrophilic Aromatic Substitutions
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Regioselectivity in Electrophilic Aromatic Substitutions
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
Organic Reaction Mechanisms
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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
Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
Competition of SN2 and E1cb/E2 Reactions
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p
141Organic Reaction Mechanisms
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
142Organic Reaction Mechanisms
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
Organic Reaction Mechanisms
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