8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
1/58
Chapter 3Mechanisms of Organic Reactions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
2/58
3.1Reaction Thermodynamics and Kinetics
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
3/58
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
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
4/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
5/58
equilibrium constant KR is the ratio of reactant concentrations in equilibrium standard free reaction enthalpyGR determines the position of the equilibrium (at given temp.)
thermodyamics are concerned with the energy balance of chemical reactions
Thermodynamics of Chemical Reactions (2)
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
6/58
standard reaction enthalpyHR is negative (advantageous) if bonds in products are stronger standard reaction entropySR is positive (advantageous) if the disorder increases
thermodyamics are concerned with the energy balance of chemical reactions
Thermodynamics of Chemical Reactions (3)
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
7/58
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
8/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
9/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
10/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
11/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
12/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
13/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
14/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
15/58
change in Gibbs free energy of transition stateG leads to change in reaction rates in reality, even more drastic because lnk ~ G
Reaction Proles: Thermodynamics and Kinetics
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
16/58
Reaction Proles: Thermodynamics and Kinetics
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
17/58
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
Reaction Proles: Thermodynamics and Kinetics
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
18/58
3.2Classication of Organic Reactions
Cl i i f O i i (1)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
19/58
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
Organic Reaction Mechanisms
Cl i i f O i R i (2)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
20/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
21/58
3.3Nucleophilic Substitutions (SN Reactions)
N l hili S b tit ti (SR ti )
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
22/58
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
Organic Reaction Mechanisms
S 1 M h i R t D t i i g St i U i l l
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
23/58
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
Organic Reaction Mechanisms
E l f S1 R ti
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
24/58
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
Organic Reaction Mechanisms
Analogy of S1 Reactions and Acid Base Reactions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
25/58
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
Organic Reaction Mechanisms
RLGR
R
+ LGR
RR
H LG + LGH
SN1 reaction
acid-base reaction
Brsted acid
Brsted acid leaving group
conjugate base
Leaving Group Quality
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
26/58
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
Organic Reaction Mechanisms
Trivial Names and Abbreviations of Important Leaving Groups
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
27/58
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
Organic Reaction Mechanisms
Stabilization of the Carbocation Intermediate (1)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
28/58
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
Stabilization of the Carbocation Intermediate (1)
116
triphenylmethyltrityl
diphenylmethyl
phenylmethylbenzyl
ethenylmethylallyl
tertiarycarbon
secondarycarbon
primarycarbon
phenyl(sp2)
Organic Reaction Mechanisms
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
Stabilization of the Carbocation Intermediate (2)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
29/58
the more delocalization (donor groups, larger aromatic systems), the better stabilization
stabilization by resonance (+M eff ect)
Stabilization of the Carbocation Intermediate (2)
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
Organic Reaction Mechanisms
Stabilization of the Carbocation Intermediate (3)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
30/58
the more alkyl groups (the higher substituted), the better stabilized is carbocation
stabilization by inductive eff ects (+I eff ect); conceptual explanation by hyperconjugation
Stabilization of the Carbocation Intermediate (3)
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
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
33/58
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
Organic Reaction Mechanisms
Nucleophilic Reactions on Carbonyl Compounds
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
34/58
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
Organic Reaction Mechanisms
Nucleophilic Substitution on Carbonyl Compounds: AdditionElimination Mechanism (SAE)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
35/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
36/58
Examples for Nucleophilic Substitutions on Carbonyl Carbons
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
37/58
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
Organic Reaction Mechanisms
Example: Peptide Coupling Reactions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
38/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
39/58
3.4Electrophilic Additions to Olens (AE Reactions)
Reactions of Olens with Electrophiles
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
40/58
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)
Organic Reaction Mechanisms
Examples
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
41/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
42/58
Regioselectivity of Electrophilic Additions: Markovnikov-Rule
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
43/58
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)
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
44/58
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
45/58
3.5Electrophilic Substitutions on Aromatic Compounds
Multiple Bonds Aromatic Compounds Do Not React Like Olens
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
46/58
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
Organic Reaction Mechanisms
Examples
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
47/58
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
Organic Reaction Mechanisms
Mechanism of Electrophilic Aromatic Substitutions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
48/58
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
Organic Reaction Mechanisms
Regioselectivity in Electrophilic Aromatic Substitutions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
49/58
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
Organic Reaction Mechanisms
Regioselectivity in Electrophilic Aromatic Substitutions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
50/58
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
Organic Reaction Mechanisms
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
51/58
3.6Elimination Reactions
-Hydrogen Eliminations
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
52/58
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
Organic Reaction Mechanisms
Competition of SN1 and E1 Reactions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
53/58
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
Organic Reaction Mechanisms
Competition of SN2 and E1cb /E2 Reactions
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
54/58
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
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
55/58
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
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
56/58
3.7Radical Substitutions and Additions
Radical Substitution Reactions (SR)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
57/58
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
Organic Reaction Mechanisms
Radical Addition Reactions (AR)
8/12/2019 organic reaction mechanismsdjfsdnfksdjfnskjdfnsknfksd
58/58
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