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651.06
221
Electrophilic Addition to Alkenes & Alkynes
YX Y X X Y
This is a classical & apparently straightforward reaction
Questions: 1) stereochemistry
2) regiochemistry
3) mechanism
Stereochemistry of Addition
case A: H _ X
BrBr
H Br +
anti syn
9 1:
H H
Hammond, JACS 1954, 76, 4121
This is often (but not universally) true for unconjugated alkenes
Why?
1) kinetics are often termolecular: r = k3[alkene][H-X]2
implication:
H X
XH -simultaneous addition of two H-X
molecules
⇒sterically favors anti
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2) torsional strain
consider the transition states for syn & anti addition:
H
XH X
vs.
anti syn
anti
syn
staggered (favored)
eclipsed (disfavored)
Case B -Halogen Addition
Br2+
Br
Br
trans
Br2Br
Br
Br
Br
Br
Br
anti in sense of addition
H3CHCH2C
F
Br H3CHC CH2
BrSO2, -60o+
SbF5SbF6
⇑ can be observed by NMR
addition of Cl2, largely similar
addition of F2, degrades carbon chain
addition of I2, readily reversible (favors s.m.)
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other electrophiles:
sulfur / selenium
RCH CH2RCH CH2
S
R CH
SR
CH2
Cl
RCH CH2
S
ClR
+
R
sulfonium ion
sulfurane
RSCl
ClSN2
similar behavior for RSeCl
Iodination
While diiodo products are not stable, iodine is still a very useful electrophile -
iodolactonizations
OH O O O
I
O OH
I I
OH O
preference for five membered over six membered ring
O
O
OH
I
OH
O
O
OH
O
O
II
I
O
I2, I
6 memberedcyclization
H
H
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Addition of Metals
NaBH4
Hg(OAc)2
AcO-
Hg
O
O
Hg
O
O
O
O
Markownikoff regioselectivity and stereoselectivity
comparison of bridged cationic intermediates
H
a) H+ is a hard acid with no unshared electrons
b) either carbocation or hydrogen bridged cation is electron deficient
Br
a) Br+ is a soft acid
b) Bromonium ion can be represented having two covalent bonds to
bromine
Hg
a) Hg++ is a soft acid - strongly polarizing
b) electron deficient bridged structure
c) extent of bridging Br+ > Hg++ > H+
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Addenda
a variety of nucleophiles can participate in mercuration
R
R
NH
1) Hg(ClO4)2,
2) NaBH4
NH2
Second reduction step is not a trivial consideration
RHgX + NaBH4 → RHgH
RHgH → R. + IHgH
R. + RHgH → RH + Hgo + R.
Reduction with sodium borohydride is a radical process
Reduction with Na-Hg in protic solvent does not involve radical intermediates
Acetylenes & Allenes
AdE2
R R X Y RX
R
X
R
R
Y
Y
R
X
R
+
Y
R R
X Y
R R
XX
R
R
YY
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AdE3
R R
X
R
R
Y
X Y
X Y X
Y
In general, alkynes are much less reactive towards electrophiles than alkenes
R H RX
H
Xmuch less stable
R CH
CH2 R CH
XCH2X
Reaction Rxn. rate ratio terminal alkenes / alkynes
bromination 2 x 105
chlorination 5 x 105
H+ / hydration 4
Addition is Markownikoff
Impact of substitution:
syn
Cl
HCl
H
C C H + C C H
Cl H
H
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anti
C C CH3 +H3C C C CH3H3C
H Cl
H Cl
H
CH3
H3C
Cl
HCl
H2C C CH2
H2C CH
CH2
H3C C CH2
?+ HX
HH+
C C CH
HH
HC C C
H
HH
H
unstabilized primary carbocation
HCl
HCl
H2C C CH2 H3CCH2
Cl
H3C CH3
Cl
Cl
+
Hydroboration
CH3 H3C H3CH
BOH
H1) B2H6 2) H2O2
H
H
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C-B Bond Formation
regioselectivity: anti-Markownikoff addition
stereoselectivity: syn addition
H
C1C2
BR
R
C1 donates electrons to the empty orbital on boron while hydrogen
on boron donates electrons back to C2 on the alkene
NOTE: Hydrogen is not the electrophilic portion of the attacking group
concerted reaction dominated by steric interactions:
(BH3)2 43% 57%
HB
0.2% 99.8%
C-B Bond Breakage
R B
R
R
O OH R B
R
OR
RO B
OR
OR
R3B HOO+ + OH
H2OROH + B(OH)3
replacement of C-B bond with retention of configuration
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Elimination Reactions
E2
BH
X
H
R
RR
R
!
!
R
R
R
R
+
B
E1
X
H
R
RR
R
R
R
R
R
+
X
H
R
RR
RBH
B
E1cb
BHB
X
H
R
RR
R
R
R
R
R
+XR
RR
RX
α elimination:
R C X
H
R
R C
R
HX+
β elimination:
R R
XH
H H
RCH CHR + HX
γ elimination:
R CH
CHCH
R
R R
+ HX
H H X
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Regioselectivity:
E1 relative stability of product alkene is determining factor (gives more highly
stabilized olefin) ⇒reactions are of low regioselectivity
E1cb determined by kinetic acidity of β protons
alkyl substituents electronically and sterically retard proton removal
⇒ preferred formation of less substituted olefin
Saytzeff Rule: eliminations involving good leaving groups give more substituted olefin
Hofmann Rule: eliminations involving poor leaving groups give less substituted olefins
Stereochemistry:
anti elimination dominates particularly with good leaving groups
(syn elimination is possible and is important with poor leaving groups)
Ion pair hypothesis:
C C
H X
OR
M base & cation assist in departure of leaving group
syn elimination higher in benzene
anti elimination higher in DMSO
651.06
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Most reactions are neither pure E1, E2 or E1cb, but rather lie somwhere on a continuum between all 3. The question is how to visualize such a scenario...
X-
R1
H
X
R3 R4R2
B- +
E2E1cb
E1
C-H
bond c
leavage
C-X bond cleavage
R1X
R3 R4R2
BH +
R1
H
R3 R4R2
B- +
R1 R4
R3R2
+ BH
+ X-
but, most reaction pathways will lie in between these extrema:
TS1 TS2
TS2
TS1
C-H
bon
d c
leavag
e
C-X bond cleavage
E1cb/E2
E1/E2
these transition states will have differing amountsof bond breaking:
!-
R1R2
R4R3
H
X
B!- ‡
!+
R1R2
R4R3
B" ‡
X!-
H
If we add energy as a third dimension, these are known as More-O’Ferral diagrams
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Other β-Elimination Reactions
R OH
OH
H
(-H2O)
hydrate
R H
O
aldehyde
R OH
NH
H
(-H2O)
hemiaminal
R H
N
aldimine
R'R'
Another important version - alcohol oxidation
R R'
OHX+
(-H+) R R'
OX
H :B (-BH)
(-X-) R R'
O
X= R2S, CrO3, Cl, Br (for example)
• This is the predominant mechanism by which alcohols are oxidized to carbonyl compounds
Ex:
R OH1. (COCl)2, DMSO, -45°2. NEt3, -45° -> 0°
RCHO "Swern oxidation"
mechanism:
H3CS+
CH3
O-
+ Cl
O
O
Cl
H3CS+
CH3
ClCl-
+
R
O
HSN2
H3CS+
CH2
O
R
Cl-
H NEt3
H3CS+
CH2
O
RHH
ylide
!-elim.
-45° -> 0°
H3CS
CH3
O
R
H
(- Et3NH+ -Cl)
• This is also true for CrVI oxidations (H2CrO4, etc.) and most other common oxidants
651.06
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Fragmentation Reactions These are β-elimination reactions accompanied by cleavage of a carbon-carbon bond Grob (Wharton) Fragmentation
B-
O XH
O
+ + B+H
-X
- there are stereochemical requirements placed on this reaction:
KOH
KOH
OTs
OH O
OTs
OH
A)
B) no reaction
Why? Look at the conformations:
X
O-
X
O-
leaving group is anti to breaking C-C bond
leaving group is gauche to breaking C-C bond
A)
B)
The requirement for the anti relationship in the Grob is akin to the anti preference of the E2 Eschenmoser Fragmentation
O
NNHTs
H+, !
O
A. Eschenmoser, Helv. Chim. Acta
mechanism:
H+O
N N H
Ts
O
NN
Ts
H
O
-only works for cyclic epoxy ketones