Carbon-Carbon Bond
Formation and
Synthesis
24-1
Organometallic Compounds
 Recall:
two extremely important reactions of
metals and organometallic compounds:
• Oxidative addition: The addition of a reagent to a metal
center causing it to add two substituents which extract
two electrons from the metal and increasing its
oxidation state by two.
• Reductive elimination: The elimination of two
substituents which donate two electrons to the metal
center causing the oxidation state of the metal to
decrease by two.
oxid ative
add ition X
MLn + X2
MLn
reductive X
elimin ation
24-2
Heck Reaction
Overall: A palladium-catalyzed reaction in which
the R group of RX, a haloalkene or haloarene, is
substituted for a vinylic H of an alkene.
H
R-X
+
Haloalk ene Alken e
or Haloarene
+
B
Pd catalys t
Heck reaction
Base
R
+
Subs tituted
alken e
BH+ X-
Conjugate acid
of the b ase
24-3
Heck Reaction (consider the alkene)
• Substitution (H  R) is highly regioselective; most
commonly at the less substituted carbon of the double
bond.
• Substitution is highly stereoselective; the E
configuration is often formed almost exclusively.
O
Br
Bromobenzen e
+
CH2 =CHCOCH3
Meth yl 2-p ropen oate
(Methyl acrylate)
Pd catalyst
Heck reaction
E
O
COCH3
Less substituted,
H  Ph
substitution
occurs here.
Neither E nor Z
Methyl (E)-3-phen yl-2-p ropenoate
(Meth yl cinnamate)
24-4
Heck Reaction (RX = Haloalkene)
• For RX = haloalkene: Reaction is stereospecific; the
configuration of the double bond in the haloalkene is
E
preserved.
Z
Z
I
+
(Z)-3-Iodo-3hexen e
Ph
Styren e
Ph
Pd catalys t
Heck reaction
(1E,3Z)-1-Phen yl-3ethyl-1,3-h exadiene
E
E
I
(E)-3-Iod o-3hexen e
+
Ph
Styren e
Ph
E
Pd catalys t
Heck reaction
(1E,3E)-1-Phenyl-3ethyl-1,3-h exadiene
24-5
Heck Reaction. Some considerations.
 The
catalyst:
•
•
•
•
most commonly Pd(II) acetate.
reduced in situ to Pd(0).
reaction of Pd(0) with good ligands gives PdL2.
The organic halogen compound: aryl, heterocyclic,
benzylic, and vinylic iodides, chlorides, bromides, and
triflates (CF3SO2O-).
• alkyl halides with an easily eliminated b hydrogen are
rarely used because they undergo b-elimination to give
alkenes.
• OH groups and the C=O groups of aldehydes, ketones,
and esters are unreactive under Heck conditions.
24-6
Heck Reaction. More…
 The
alkene
• The less the crowding on the alkene, the more reactive
it is.
 The
base
• Triethylamine, sodium, and potassium acetate, and
sodium hydrogen carbonate are most common
 The
solvent.
• Polar aprotic solvents such as DMF, acetonitrile, and
DMSO.
• aqueous methanol may also be used.
 The
ligand
• Triphenylphosphine, PPh3, is one of the most common.
24-7
Heck Reaction
Start here
L = PPh3
R- X oxidati ve
BH X
X
addi ti on
R
L 2 Pd
L 2 Pd
R4
H
1
R
B:
0
HX
II
5
redu cti ve
2
R3
R2
s
yn
e li mi n ati on
addi ti on
Th e catalytic
X
cycl e of th e
X
II
L 2 Pd II
He ck reacti on
R
L 2 Pd
+
-
H
4
R4
R2
R4
s yn
e li mi n ati on
X
II
L 2 Pd
R3
H
R2
3
rotati
on about
righ tthe
abou
t bond.
Rotation
C-C
the
C -C the
bonRd is swapped
This
is where
H
in, replacing the H.
R3
R
R4
R3
R
R2
24-8
Heck Reaction
• The usual pattern of acyclic compounds: replacement
of a hydrogen of the double bond with the R group.
• If the R group has no H for syn elimination, then a b H
may be abstracted elsewhere.
I
+
This b H should be brought
into position for syn
elimination with the Pd. Can’t
happen due to cyclohexane
ring.
Pd(OAc) 2
(C 2 H5 ) 3 N
H
PdL2 OAc
H
H
(racemic)
24-9
Suzuki Coupling
Suzuki coupling: A palladium-catalyzed reaction of an
organoborane (R’-BY2) or organoborate (RB(OMe)2) with
an alkenyl, aryl, or alkynyl halide, or triflate (R-X) to yield
R-R’.
Overall:
R'-BY2 + R-X
Organob oron
Compounds
B
RCH=CH B
Alkyl B
PdL4 , Base
R-R' + XBY2
Cou pling reagents
X = h alide or triflate)
X
RCH=CHX
RC C X
Alkyl-X
(D ifficult)
24-10
Suzuki Coupling
• Recall boranes are easily prepared from alkenes or
alkynes by hydroboration.
H
+ ( Sia) 2 BH
hydroboration
B(Sia) 2
H
• Borates are prepared from alkyl or aryl lithium
compounds and trimethylborate.
Li + B(OMe) 3
B(OMe) 2 + LiOMe
PhCl + Li
24-11
Suzuki Coupling
• These examples illustrate the versatility of the
reaction.
H
H
B(Sia) 2 + Br
C6 H1 3
H
B(OMe) 2 + Br
NH2
N
B( OMe) 2
Pd( Ph3 ) 4
NaOMe
C6 H1 3
H
Ph( OAc) 2
Na2 CO3
NH2
N
Pd( OAc) 2
+ Br
Et 3 N
24-12
Suzuki Coupling
Reductive elimination
Oxid. Addn
Transmetalation R1
and OtBu swap
Substitution
24-13
Alkene Metathesis
 Alkene
metathesis: A reaction in which two
alkenes interchange carbons on their double
bonds.
A
A
B
A
B
catalys t
+
A
A
A
B
B
A
A
+
B
B
B
B
• If the reaction involves 2,2-disubstituted alkenes,
ethylene is lost to give a single alkene product.
A
A
B
H
A
catalys t
+
H
A
B
H
H
+
B
CH2=CH2
B
24-14
Alkene Metathesis
• A useful variant of this reaction uses a starting
material in which both alkenes are in the same
molecule, and the product is a cycloalkene.
EtOOC
COOEt
EtOOC
catalys t
COOEt
+ CH2 = CH2
• Catalysts for these reactions are a class of
compounds called stable nucleophilic carbenes.
24-15
Stable Nucleophilic Carbenes
• Carbenes and carbenoids provide the best route to three
membered carbon rings.
• Most carbenes are highly reactive electrophiles.
• Carbenes with strongly electron-donating atoms, however, for
example nitrogen atoms, are particularly stable.
• Rather than being electron deficient, these carbenes are
nucleophiles because of the strong electron donation by the
nitrogens.
• Because they donate electrons well, they are excellent ligands
(resembling phosphines) for certain transition metals.
• The next screen shows a stable nucleophilic carbene.
24-16
Nucleophilic Carbene
• A stable nucleophilic carbene.
N
N
N
–
N
+
N
–
N+
24-17
Alkene Metathesis Catalyst
• A useful alkene methathesis catalyst consists of
ruthenium, Ru, complexed with nucleophilic carbenes
and another carbenoid ligand.
• In this example, the other carbenoid ligand is a
benzylidene group.
R
N
n u cle ophi l ic
carbe n e s
N
R
Cl
Cl
R
N
Ru
C6H5
N
R
24-18
Ring-Closing Alkene Metathesis
 Like
the Heck reaction, alkene metathesis
involves a catalytic cycle:
• Addition of a metallocarbenoid to the alkene gives a
four-membered ring.
• Elimination of an alkene in the opposite direction gives
a new alkene.
24-19
Ring-Closing Alkene Metathesis
24-20
Ring-Closing Alkene Metathesis
Initiation Step
Cycle
start
24-21
Diels-Alder Reaction
 Diels-Alder
reaction: A cycloaddition reaction of
a conjugated diene and certain types of double
and triple bonds.
• dienophile: Diene-loving.
• Diels-Alder adduct: The product of a Diels-Alder
reaction.
O
O
+
1,3-Butadie n e 3-Bu te n -2-on e
(a die n e )
(a die n oph i le )
Di e ls -A lde r addu ct
24-22
Diels-Alder Reaction
• Alkynes also function as dienophiles.
COOEt
COOEt
+
COOEt
1,3-bu tadi e n e
Di eth yl
(a die n e )
2-bu tyn e dioate
(a die n oph i le )
COOEt
Di el s -Al der addu ct
• Cycloaddition reaction: A reaction in which two
reactants add together in a single step to form a cyclic
product.
24-23
Diels-Alder Reaction
• We write a Diels-Alder reaction in the following way:
Di en e Di en oph il e
Addu ct
• The special value of D-A reactions are that they:
1. form six-membered rings.
2. form two new C-C bonds at the same time.
3. are stereospecific and regioselective.
Note the reaction of butadiene and ethylene gives only
traces of cyclohexene.
24-24
Diels-Alder Reaction
• The conformation of the diene must be s-cis.
s-t rans
conformation
(lower in energy)
s-cis
conformation
(higher in energy)
24-25
Diels-Alder Reaction Steric Restrictions
• (2Z,4Z)-2,4-Hexadiene is unreactive in Diels-Alder
reactions because nonbonded interactions prevent it
from assuming the planar s-cis conformation.
methyl grou ps
forced clos er th an
allow ed by van
der Waals radii
s-t rans conformation
s-cis conformation
(low er energy)
(h igh er energy)
(2Z,4Z)-2,4-Hexadiene
24-26
Diels-Alder Reaction
• Reaction is facilitated by a combination of electronwithdrawing substituents on one reactant and
electron-releasing substituents on the other.
200°C
pre s s u re
+
1,3-Bu tadie n e Eth yl en e
C ycloh e xen e
O
O
140°C
+
1,3-Bu tadie n e 3-Bu te n -2-on e
O
O
+
2,3-Di me th yl - 3-Bu te n -2-on e
1,3-bu tadie n e
30°C
24-27
Diels-Alder Reaction
Ele ctron -Re l e as i n g
Grou ps
Ele ctron -W i th drawi n g
Grou ps
- CH 3 , alkyl group s
- CH O (ald ehyde, ketone)
- OR (ether)
- COOH (carb oxyl)
- OOCR (es ter)
- COOR (es ter)
- NO 2 (nitro)
-C
N (cyano)
24-28
Diels-Alder Reaction
• The Diels-Alder reaction can be used to form bicyclic
systems.
+
room
tem peratu re
Di en e Di en oph i le
170°C
H
H
Di cyclope n tadie n e
(en do form )
24-29
Diels-Alder Reaction
• Exo and endo are relative to the double bond derived
from the diene.
the dou bl e bon d
de ri ve d from
the di e n e
e xo (ou tsi de)
e n do (i n si de )
rel ati ve to
the dou bl e
bon d
24-30
Diels-Alder Reaction
• For a Diels-Alder reaction under kinetic control, endo
orientation of the dienophile is favored.
O
+
Cyclopentadiene
OCH3
Methyl
propenoate
7
COOCH 3
H
redraw 6
5
4
1 2
3
COOCH 3
Me th yl bi cyclo[2.2.1]h e pt-5-e n e n do-2-carboxylate
(racem ic)
24-31
Diels-Alder Reaction
• The configuration of the dienophile is retained.
COOCH 3
COOCH 3
+
COOCH 3
A cis
die n oph il e)
H3 COOC
COOCH 3
Di me th yl cis-4-cycl oh exe n e 1,2-di carboxylate
COOCH 3
+
COOCH 3
A trans
die n oph il e)
COOCH 3
Di me th yl trans- 4-cycl oh exe n e 1,2-di carboxylate
(racem ic)
24-32
Diels-Alder Reaction
• The configuration of the diene is retained.
CH3
O
+
H3 C
O
CH3
H3 C
CH3
O
H3 C
H
O
H
O
O
O
CH3
O
O
O
O
+
H
H3 C
H
O
24-33
Diels-Alder Reaction
 Mechanism
• No evidence for the participation of either radical of
ionic intermediates.
• Chemists propose that the Diels-Alder reaction is a
concerted pericyclic reaction.
 Pericyclic
reaction: A reaction that takes place in
a single step, without intermediates, and involves
a cyclic redistribution of bonding electrons.
 Concerted reaction: All bond making and bond
breaking occurs simultaneously.
24-34
Diels-Alder Reaction
• Mechanism of the
Diels-Alder reaction
24-35
Aromatic Transition States
 Hückel
criteria for aromaticity: The presence of
(4n + 2) pi electrons in a ring that is planar and
fully conjugated.
 Just as aromaticity imparts a special stability to
certain types of molecules and ions, the
presence of (4n + 2) electrons in a cyclic
transition state imparts a special stability to
certain types of transition states.
• Reactions involving 2, 6, 10, 14.... electrons in a cyclic
transition state have especially low activation energies
and take place particularly readily.
24-36
Aromatic Transition States
• Decarboxylation of b-keto acids and b-dicarboxylic
acids.
O
H
O
H
O
O
C
O
(A cycl ic s i x-me mbe re d
tran s i ti on s tate )
O
+ CO 2
O
e n ol of
a k e ton e
• Cope elimination of amine N-oxides.
C
H
C
CH3 heat
N+
O
CH3
A cyclic six -membered
transition state
CH3
C
C
An alkene
+ H
N
O
CH3
N,N-dimethylhydrox ylamine
24-37
Aromatic Transition States
• the Diels-Alder reaction
Di en e Di en oph il e
Addu ct
• pyrolysis of esters (Problem 22.42)
 We
now look at examples of two more reactions
that proceed by aromatic transition states:
• Claisen rearrangement.
• Cope rearrangement.
24-38
Claisen Rearrangement
 Claisen
rearrangement: A thermal rearrangement
of allyl phenyl ethers to 2-allylphenols.
O
OH
200-250°C
Allyl ph enyl ether
2-A llylp henol
24-39
Claisen Rearrangement
O
O
h e at
Al lyl ph en yl
e th e r
Tran s ition
s tate
OH
O
k e to-e n ol
tau tome ri s m
H
A cycloh e xadi en on e
i n te rme diate
o-Al lyl ph en ol
24-40
Cope Rearrangement
 Cope
rearrangement: A thermal isomerization of
1,5-dienes.
heat
3,3-Dime th yl1,5-he xadie n e
2-Meth yl-2,6h e ptadi e n e
24-41
Cope Rearrangement
Example 24.8 Predict the product of these Cope
rearrangements.
350°C
(a)
OH
320°C
(b)
H
24-42
Synthesis of Single Enantiomers
• We have stressed throughout the text that the
synthesis of chiral products from achiral starting
materials and under achiral reaction conditions of
necessity gives enantiomers as a racemic mixture.
• Nature achieves the synthesis of single enantiomers
by using enzymes, which create a chiral environment
in which reaction takes place.
• Enzymes show high enantiomeric and diastereomeric
selectivity with the result that enzyme-catalyzed
reactions invariably give only one of all possible
stereoisomers.
24-43
Synthesis of Single Enantiomers
 How
do chemists achieve the synthesis of single
enantiomers?
 The most common method is to produce a
racemic mixture and then resolve it. How?
• the different physical properties of diastereomeric
salts.
• the use of enzymes as resolving agents.
• chromatographic on a chiral substrate.
24-44
Synthesis of Single Enantiomers
• In a second strategy, asymmetric induction, the achiral starting
material is placed in a chiral environment by reacting it with a
chiral auxiliary. Later it will be removed.
• E. J. Corey used this chiral auxiliary to direct an asymmetric
Diels-Alder reaction.
• 8-Phenylmenthol was prepared from naturally occurring
enantiomerically pure menthol.
Me
HO
Me
several
step s
Me
Menth ol
(enan tiomerically p ure)
Ph
Me
Me
HO
Me
8-Phen ylmenthol
(an enan tiomerically
pure chiral auxillary)
24-45
Synthesis of Single Enantiomers
• The initial step in Corey’s prostaglandin synthesis was
a Diels-Alder reaction.
• By binding the achiral acrylate with enantiomerically
pure 8-phenylmenthol, he thus placed the dienophile in
a chiral environment.
• The result is an enantioselective synthesis.
Me
OBn
Ph
Me
O
+
O
Achiral
Me
Enantiomerically
pure
D iels-A lder
89%
BnO
OBn
+
O
97%
OR
RO
O
3% 24-46
Synthesis of Single Enantiomers
• A third strategy is to begin a synthesis with an
enantiomerically pure starting material.
• Gilbert Stork began his prostaglandin synthesis with
the naturally occurring, enantiomerically pure Derythrose.
• This four-carbon building block has the R
configuration at each stereocenter.
• With these two stereocenters thus established, he then
used well understood reactions to synthesize his
target molecule in enantiomerically pure form.
OH O
HO
H
OH
D-Erythrose
24-47