Minggu ke-8

Racemic Products
If optically inactive reagents combine to form a chiral
molecule, a racemic mixture of enantiomers is
formed.
Racemic Mixture
Racemic mixture (d,l;): an equimolar mixture (50:50)
of two enantiomers
because a racemic mixture contains equal numbers of
dextrorotatory and levorotatory molecules, its specific
activity is zero.
The mixture may have different b.p. and m.p. from the
enantiomers!


a sample that is optically inactive can be
either an achiral substance or a racemic
mixture
Optical Activity
Some mixtures are neither optically pure (all one
enantiomer) nor racemic (equal mixture of both
enantiomers).

Optical purity:
Ratio of the rotation of a mixture to the rotation of a
pure enantiomer

o.p. = observed rotation x 100%
rotation of pure enantiomer
Optical Activity
Example: (-)-2-butanol has a specific rotation of - 13.5
o
while the specific rotation of (+)-2-butanol is +13.5
o
.
Calculate the optical purity of a mixture containing (+)
and (-)-2-butanol if the mixture has an observed
rotation of 8.55
o
. Does the mixture contain more (+)
or more (-)-2-butanol?
o.p = -8.55
o
x 100% = 63.3%
-13.5
o

Optical Activity
Another method to express (or determine) the relative
amounts of enantiomers present in a mixture is
enantiomeric excess.
Numerically identical to optical purity

e.e. = o.p. = excess of one over the other x 100%
entire mixture


% 100 . . x
l d
l d
e e
+

=
Optical Activity
Example: Calculate the e.e of a mixture containing 25%
(+)-2-butanol and 75% (-)-2-butanol if the specific
rotation of (+)-2-butanol is 13.5
o
.
% 100 . . x
l d
l d
e e
+

=
% . 50 % 100
100
50
% 100
75 25
75 25
. . =

=
+

= x x e e
Optical Activity
Example: Calculate the relative proportions of (+)-2-
butanol and (-)-2-butanol required to give a specific
rotation of +0.45
o
.
o.p. = +0.45
o
x 100% = 3.3%
+13.5
o

% 3 . 3 % 100 . . =
+

= x
l d
l d
e e
So: d - l = 3.3
d + l = 100
Add both equations:
2d = 103.3 d = 51.65% = 52%
l = 48.35% = 48%
Enantiomeric excess
We can use the observed optical rotation to
determine the relative amounts of R and S
enantiomers in a mixture. The optical purity of a
mixture is referred to as the enantiomeric excess
(ee), with 100% ee referring to a pure enantiomer
and 0% ee referring to a racemic mixture
Enantiomeric excess
The enantiomeric excess (ee) is given by:

[o]
D
(observed) [R] [S]
[o]
D
(pure) [R] + [S]
=
Using 2-chloro-1-phenylethanol as an example, what would be the
enantiomeric excess if the sample we made had an observed
optical rotation of -35.
-35/-50 = 0.70 = ([R] [S])/([R] + [S]) = (x-(1-x))/1 = 2x 1 =
0.70
x = 0.85 Therefore, [R] = 85%, [S] = 15% and the ee = 70%
Calculate % Composition
The specific rotation of (S)-2-iodobutane is
+15.90. Determine the % composition of a
mixture of (R)- and (S)-2-iodobutane if the
specific rotation of the mixture is -3.18.


Resolution of Enantiomers
React a racemic mixture with a chiral compound to
form diastereomers, which can be separated.
=>

Stereochemistry and Reactivity
(Study of stereochemistry change)
Minggu ke-9
Stereochemistry and Reactivity
Most reactions of alkenes generate a chiral center
OH
H 1. Hg(OAc)
2
2. NaBH
4
chiral carbon
Alcohol is prepared as a racemic mixture
Why?
Racemic Mixture Forms
Addition of Hg(II) gives
rise to two cations
Addition of water gives
rise to both
enantiomers
H
H
H Hg
+
H
H
H
Hg
+
O
H H
O
H H
Reactions with Chiral Substrates
Reaction goes through chiral carbocation
Provides some stereochemical preference
Do not observe a 50:50 mixture
Products are diastereomeric
CH
3
H
CH
3
H
H
OH
The Synthesis of Chiral Molecules
Most chemical reactions which produce chiral
molecules produce them in racemic form
20
General Rule
Reactions of chiral substrates with:
An achiral reactant gives unequal amounts of
diastereomers
A chiral reactant gives a chiral product

Reactions of achiral substrates with
An achiral reactant gives an achiral product
Prochirality
A molecule that is achiral but that can become
chiral by a single alteration is a prochiral molecule






Prochiral Distinctions: Faces
Planar faces that can become tetrahedral are different
from the top or bottom
A center at the planar face at a carbon atom is
designated re if the three groups in priority sequence
are clockwise, and si if they are counterclockwise



Prochiral distinctions, paired atoms or
groups
An sp
3
carbon with two groups that are the same is a
prochirality center
The two identical groups are distinguished by considering
either and seeing if it was increased in priority in
comparison with the other
If the center becomes R the group is pro-R and pro-S if the
center becomes S




Designation
pro-R: replaced atom leads to R configuration

pro-S: replaced atom leads to S configuration
Terminologies Associated with
Stereochemistry
pro-R-hydrogen
pro-S-hydrogen
Enantiotopic hydrogens have the same chemical
reactivity and cannot be distinguished by achiral agents,
but they are not chemically equivalent toward chiral
reagents

Diastereotopic atom
A pair of like atoms (or group of atom) that are not
symmetry- equivalent, where substitution of one by a
different group (i.e. desymmetrization) leads to a
diastereomer of molecule obtained by like substitution of
the other atom (or group of atoms).
Diastreotopic atoms = different reactivity, different
electronic enviroment different NMR
Diastereotopic hydrogens do not have the same reactivity
with achiral reagents
Diastereotopic hydrogens do not have the same reactivity
with achiral reagents
Biological Chemistry
Many biological reactions involve prochiral centers

Chiral centers are extremely important in biological
processes and drug development
Biological Chemistry
Enzymes yield a single enantiomer
Enzymes are chiral and induce chirality
A regioselective reaction: preferential formation of one
constitutional isomer
A stereoselective reaction: preferential formation of a
stereoisomer
A stereospecific reaction: each stereoisomeric reactant
produces a different stereoisomeric product or a different
set of products
All stereospecific reactions are stereoselective
Not all stereoselective reactions are stereospecific
Many reactions convert achiral
reactants to chiral products.
If all of the components of the starting state (reactants,
catalysts, solvents, etc.) are achiral, any chiral products
that will be formed are racemic mixtures.
"Optically inactive starting materials can't give optically active
products."
In order for a substance to be optically active, it must be
chiral and one enantiomer must be present in greater
amounts than the other.
Addition Reactions
Electrophilic addition (alkenes group)
Nucleophilic addition (carbonyl group)
Addition Reactions
CH
3
CH
2
CH CH
2
ether
CH
3
CH
2
CHCH
3
Br
achiral
chiral
H Br
Addition of HBr
Br
-
Br
-
C
CH
3
CH
2
Br
H
CH
3
C
CH
3
CH
2
Br
H
CH
3
CH
3
CH
2
C
CH
3
H
CH
3
CH
2
CH CH
2
ether
H Br
CH
3
CH
2
C
CH
3
H
Addition of HBr to a Chiral Alkene
Chiral intermediate is not attacked equally from top
and bottom because of steric reasons. Therefore, a
mixture of product is formed in unequal amounts.
Addition of HBr to a Chiral Alkene
CH
3
H
HBr
C CH
3
CH
3
H H
Br
-
CH
3
CH
3
H
Br
H
CH
3
CH
3
H Br H
2S,4R 2R,4R
Addition of Br
2
Cis





Racemic mixture
Achiral bromonium ion
C C
H H
CH
3
CH
3
Br
Br
C C
H H
CH
3
CH
3
Br
2
C C
H H
CH
3
CH
3
Br
Br
-
a
C C
H H
CH
3
CH
3
Br
Br
a
b
b
a
b
Addition of Br
2
Trans

Symmetry plane, therefore meso
Models are superimposible
C C
Br
Br
H
H
3
C
CH
3
H
b a
C C
Br
H
H
3
C
CH
3
H
Br
a
Br
-
C C
H
CH
3
Br
H
CH
3
Br
2
C C
H
CH
3
H
CH
3
b
a b
Addition of Br
2
C C
Br
Br
H
H
3
C
CH
3
H
C C
Br
H
H
3
C
CH
3
H
Br
C C
Br
H
3
C
H
CH
3
H
Br
Regioselectivity
If Br
2
is added to propene there is no regioselectivity issue.
Br
2
Br
Br
If Br
2
is added in the presence of excess alternative nucleophile, such as
CH
3
OH, regioselectivity may become important.
Br - Br
OCH
3
Br
CH
3
O-H
Br
OCH
3
and/or
+ H
+
+ Br
-
+ H
+
+ Br
-
Regioselectivity - 2
Consider, again, the cyclic bromonium ion and the resonance structures.
R
Br
Weaker
bond
More positive charge
Stronger bond
Expect the nucleophile to attack here. Remember inversion occurs.
H
H
RCO
3
H
H
H
O
H
H
O
+
minor
major
OsO
4
O O
O O
Os
O O H
H
H
2
S
Syn-addition
KMnO
4
cis
trans
stereospecific
syn addition
R,S S,R
(erythro)
enantiomers (racemic)
S,S R,R
(threo)
C C
HO OH
H Et
Me H
C C
HO OH
H Et
Me H
+
C C
HO OH
H H
Me Et
C C
HO OH
H H
Me Et
+
Reaction Involving KMnO
4
KMnO
4
OH
OH
H
H
H
OH
H
OH
+
exo
major
endo
minor
O
Et
Me
Nu
-
O
-
Me
Et
Nu
-
O
-
Me
Et
Nu
-
+
Me
H
Me
H
O
Me
H
Me
H
OH
H
Me
H
Me
H
OH
H
path a
path b
+
(2S,3S)
(1R,2S,3S)
major
(1S,2S,3S)
NaBH
4
Ph
O
Me Et
minor
major
Ph
Me Et
R OH
Ph
Me Et
HO R
re
si
diastereotopic
center
Crams Rule:
(empirical)
L
S
M
O
R
Nu
-
when carbonyl is flanked by
the S and M groups, the
preferred attack is on the side
with the smallest substituent
enantiomers
C(+) C(-)
2R(+)
C(+)R(+) C(-)R(+)
diastereomers
C(+)R(+)
C(-)R(+)
R(+)
R(+)
C(+)
C(-)
Strategy
Chiral Synthetic Approach
Stereoselective or asymmetric syntheses
Biotransformation or Enzymatic resolution
Catalytic enantioselective processes
Racemic Approach
Crystallization
Chiral salt resolution
CE (capillary electrophoresis)
SMB (simulated moving bed technology)
Chromatography (HPLC, SFC)
Approaches to Pure Enantiomers
Few Samples
Large Scale
Many Samples
Small Scale
Chromatographic
Resolution of Enantiomers
Non-polar
molecules
have no
affinity for
the polar
nature of the
silicate
groups on
silica gel and
can be
washed right
through the
column with a
relatively
non-polar
solvent
Polar
molecules can
form non-
covalent
attachments
to the silicate
groups, but
can be
washed
through the
column later
with a more
polar solvent
CH
3
CH
3
C
O
N
H
H
Hydrogen
bonding
Column Chromatography
Chiral Chromatography
Chiral Recognition: Ability of chiral stationary phase, CSP, to
interact differently with each enantiomer to form transient-
diastereomeric complexes; requires a minimum of 3 interactions
through:

H-bonding
- interactions
Dipole stacking
Inclusion complexing
Steric bulk




Five general types of CSPs used in chromatography:
1. Polymer-based carbohydrates
2. Pirkle or brush-type phases
3. Cyclodextrins
4. Chirobiotic phases
5. Protein-based


CSP Biphenyl derivative
H
N
C N
H
C NO
2
NO
2
O
O
The silica gel is functionalized
with a chiral substituent derived
from amino acids
R-entantiomer
When a racemic mixture of R and S
enantiomers is passed through this chiral
column, the R enantiomer has less affinity for
the stationary phase and will elute before the
S entaniomer, allowing for separation of the
entantiomers
Chiral Column Chromatography
Classification of Chiral Stationary Phases (CSP)
1) Polymer-based Carbohydrates
Chiral polysaccharide derivatives, i.e. amylose and
cellulose, coated on a silica support
Enantiomers form H-bonds with carbamate links
between side chains and polysaccharide backbone
Steric restrictions at polysaccharide backbone may
prevent access of one of enantiomers to H-bonding site
Can be used with normal phase HPLC, SFC, RP-HPLC
Limitations: Not compatible with a wide range of
solvents other than alcohols
Available columns:
i.e. Chiralpak AD, AD-RH, AS, AS-RH, and Chiralcel OD, OD-RH, OJ, OJ-RH,
etc. from Chiral Technologies, Inc.
Chiralpak IA and IBsame chiral selectors as AD and OD, respectively, but
these are immobilized on the silica; more robust and has much greater
solvent compatibilities
Classification of Chiral Stationary Phases (CSP)
2) Pirkle or Brush-type Phases: (Donor-Acceptor)
Small chiral molecules bonded to silica
More specific applications; strong 3-point interactions through 3 classes:
-donor phases
-acceptor phases
Mixed donor-acceptor phases
Binding sites are -basic or -acidic aromatic rings (- interactions),
acidic and basic sites (H-bonding), and steric interaction
Separation occurs through preferential binding of one enantiomer to CSP
Mostly used with normal phase HPLC, SFC. May get less resolution with
RP-HPLC; compatible with a broad range of solvents
Limitations: only works with aromatic compounds
Available columns:
Whelk-O 1, Whelk-O 2, ULMO, DACH-DNB (mixed phases), o-
Burke 2, -Gem 1 (-acceptor phases), Naphthylleucine (-
donor phases), from Regis Technologies, Inc.
Phenomenex Chirex phases
3) Cyclodextrin CSPs
Alpha, beta and gamma-cyclodextrins bond to silica and form
chiral cavities
3-point interactions by:
Opening of cyclodextrin cavity contains hydroxyls for H-
bonding with polar groups of analyte
Hydrophobic portion of analyte fits into non-polar cavity
(inclusion complexes)
One enantiomer will be able to better fit in the cavity than the
other
Used in RP-HPLC and polar organic mode
Limitations: analyte must have hydrophobic or aromatic group
to fit into cavity
Available columns:
Cyclobond (o-, |-, and -cyclodextrins) from Astec, Inc.
ORpak CDA (o), ORpak CDB (|), ORpak CDC () from JM Sciences
Classification of Chiral Stationary Phases
(CSP)
4) Chirobiotic Phases
Macrocyclic glycopeptides linked to silica
Contain a large number of chiral centers together
with cavities for analytes to enter and interact
Potential interactions:
- complexes, H-bonding, ionic interactions
Inclusion complexation, steric interactions
Capable of running in RP-HPLC, normal phase,
polar organic, and polar ionic modes
Available columns:
Chirobiotic V and V2 (Vancomycin), Chirobiotic T and T2
(Teicoplanin), Chirobiotic R (Ristocetin A) from Astec
5) Protein-based CSPs
Natural proteins bonded to a silica matrix
Proteins contain large numbers of chiral centers and interact
strongly with small chiral analytes through:
Hydrophobic and electrostatic interactions, H-bonding
Limitations:
Requires aqueous based conditions in RP-HPLC
Analyte must have ionizable groups such as amine or acid.
Not suited for preparative applications due to low sample
capacity
Available columns:
Chiral AGP (o-glycoprotein) from ChromTech
HSA (human serum albumin) from ChromTech
BSA (bovine serum albumin) from Regis Technologies
General use column with no solubility issues
Polymer-based phases
Specific applications; solubility issues
Pirkle-type
Chirobiotic phases
SFC only
Polymer-based, Pirkle-type, Chirobiotic
Biological Samples
Protein-based phases


Relating Configurations through Reactions in
which No Bonds to the Stereogenic Carbon are
Broken
A reaction which takes place in a way that no
bonds to the stereogenic carbon are broken
is said to proceed with retention of
configuration
Identification of enantiomer structures
Relative configuration: the relationship between
comparable stereogenic centers in two different
molecules
(R)-1-Bromo-2-butanol and (S)-2-butanol have the
same relative configuration



Absolute configuration: the actual 3-dimensional
orientation of the atoms in a chiral molecule
Can be determined by x-ray crystallography
Minggu ke-11 & 12
Alkyl halides are polarized at the carbon-halide
bond, making the carbon electrophilic
Nucleophiles will replace the halide in C-X
bonds of many alkyl halides(reaction as Lewis
base)
Nucleophiles that are also Brnsted bases can
produce elimination
In 1896, Walden showed that (-)-malic acid
could be converted to (+)-malic acid by a
series of chemical steps with achiral
reagents
This established that optical rotation was
directly related to chirality and that it
changes with chemical alteration
Reaction of (-)-malic acid with PCl
5
gives (+)-
chlorosuccinic acid
Further reaction with wet silver oxide gives (+)-
malic acid
The reaction series starting with (+) malic acid
gives (-) acid
The reactions alter the configuration at the
chirality center
The reactions involve substitution at that
center
Therefore, nucleophilic
substitution can invert the
configuration at a chirality center
The presence of carboxyl groups in malic
acid led to some dispute as to the nature of
the reactions in Waldens cycle
In the 1920s and 1930s Kenyon and Phillips
carried out a series of experiments to find out
how inversion occurs and determine the precise
mechanism of nucleophilic substitution
reactions.
Instead of halides they used tosylates (OTos)
which are better leaving groups than halides.
Rate is change in concentration with time
Depends on concentration(s), temperature,
inherent nature of reaction (activation
energy)
A rate law describes relationship between
the concentration of reactants and rate of
conversion to products determined by
experiment.
A rate constant (k) is the proportionality
factor between concentration and rate

Example: for S P
an experiment might find
Rate = k [S] (first order)
The study of rates of reactions is called
kinetics
Rates decrease as concentrations decrease
but the rate constant does not
The rate law depends on the mechanism
The order of a reaction is sum of the
exponents of the concentrations in the rate
law the example below is second order
Experiments show that for the
reaction

OH
-
+ CH
3
Br CH
3
OH + Br
-

Rate = k[OH
-
][CH
3
Br]
One type of nucleophilic substitution reaction
has the following characteristics:
Reaction occurs with inversion at reacting
center
Follows second order reaction kinetics
rate = k [Nu:
-
][RX]
The S
N
2 Reaction
The transition state of an S
N
2 reaction has a
planar arrangement of the carbon atom and
the remaining three groups.
Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Secondary might react
Tertiary are unreactive by this path
No reaction at C=C (vinyl halides)
Higher reactant
energy level (red
curve) = faster
reaction (smaller
AG

).
Higher transition-
state energy level
(red curve) =
slower reaction
(larger AG

).
The carbon atom in (a) bromomethane is readily accessible
resulting in a fast S
N
2 reaction. The carbon atoms in (b) bromoethane
(primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane
(tertiary) are successively more hindered, resulting in successively slower S
N
2
reactions.
Steric effects destabilize transition states
Severe steric effects can also destabilize ground
state
Very hindered
The more alkyl groups connected to the
reacting carbon, the slower the reaction
Neutral or negatively charged Lewis base
Reaction increases coordination at
nucleophile
Neutral nucleophile acquires positive charge
Anionic nucleophile becomes neutral
See Table 11-1 for an illustrative list
Depends on reaction and conditions
More basic nucleophiles react faster (for
similar structures. See Table 11-2)
Better nucleophiles are lower in a column of
the periodic table
Anions are usually more reactive than
neutrals
A good leaving group reduces the barrier to a
reaction
Stable anions that are weak bases are usually
excellent leaving groups and can delocalize
charge
If a group is very basic or very small, it is
prevents reaction
Solvents that can donate hydrogen bonds (-OH or
NH) slow S
N
2 reactions by associating with
reactants
Energy is required to break interactions between
reactant and solvent
Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster
reaction
Tertiary alkyl halides react rapidly in protic
solvents by a mechanism that involves
departure of the leaving group prior to addition
of the nucleophile
Called an S
N
1 reaction occurs in two distinct
steps while S
N
2 occurs with both events in same
step
If nucleophile is present in reasonable
concentration (or it is the solvent), then
ionization is the slowest step
Previously we learned that tertiary alkyl halides
react extremely slowly in S
N
2 reactions. But tert-
butyl bromide reacts with water 1,000,000 times
faster than methyl bromide.
Step through highest energy
point is rate-limiting
rate = k[RX]
The overall rate of a reaction is controlled by
the rate of the slowest step
The rate depends on the concentration of the
species and the rate constant of the step
The highest energy transition state point on
the diagram is that for the rate determining
step (which is not always the highest barrier)
This is the not the greatest difference but the
absolute highest point (Figures the same step
is rate-determining in both directions)

The planar
intermediate
should lead to
loss of
chirality
A free
carbocation
is achiral
Product
should be
racemic
Carbocation is biased to react on side
opposite leaving group
Suggests reaction occurs with carbocation
loosely associated with leaving group
during nucleophilic addition
Alternative that S
N
2 is also occurring is
unlikely
If leaving group
remains associated,
then product has
more inversion than
retention
Product is only
partially racemic
with more inversion
than retention
Associated
carbocation and
leaving group is an
ion pair
Tertiary alkyl halide is most
reactive by this mechanism
Controlled by stability of
carbocation
Delocalization of cationic charge enhances
stability
Primary allyl is more stable than primary
alkyl
Primary benzyl is more stable than allyl
Allylic and benzylic intermediates stabilized
by delocalization of charge
Primary allylic and benzylic are also more
reactive in the S
N
2 mechanism
Critically dependent on leaving group
Reactivity: the larger halides ions are better
leaving groups
In acid, OH of an alcohol is protonated and
leaving group is H
2
O, which is still less reactive
than halide
p-Toluensulfonate (TosO
-
) is excellent leaving
group
Since nucleophilic addition occurs after
formation of carbocation, reaction rate is not
affected normally affected by nature or
concentration of nucleophile
Stabilizing carbocation also stabilizes
associated transition state and controls rate
Solvation of a carbocation by
water
Polar, protic and unreactive Lewis base solvents
facilitate formation of R
+

Solvent polarity is measured as dielectric
polarization (P)
Nonpolar solvents have low P
Polar SOLVENT have high P values
Polar solvent stabilizes transition state and
intermediate more than reactant and
product
Elimination is an alternative pathway to
substitution
Opposite of addition
Generates an alkene
Can compete with substitution and decrease
yield, especially for S
N
1 processes
In the elimination of HX from an alkyl
halide, the more highly substituted alkene
product predominates

Ingold nomenclature: E elimination
E1: X
-
leaves first to generate a carbocation
a base abstracts a proton from the
carbocation
E2: Concerted (one step) transfer of a proton to a
base and departure of leaving group
A proton is transferred to base as leaving
group begins to depart
Transition state combines leaving of X
and transfer of H
Product alkene forms stereospecifically
One step rate law has base and alkyl halide
Transition state bears no resemblance to
reactant or product
Rate = k[R-X][B]
Reaction goes faster with stronger base,
better leaving group
Antiperiplanar allows orbital overlap and
minimizes steric interactions
E2 reactions must go by an anti elimination
This means that the hydrogen atom and
halogen atom must be 180
o
(coplanar) with
respect to each other!!
Draw a Newman projection formula and place
the H and X on opposite sides.
Overlap of the developing t orbital in the
transition state requires periplanar
geometry, anti arrangement
Allows orbital overlap
E2 is stereospecific
Meso-1,2-dibromo-1,2-diphenylethane with
base gives cis 1,2-diphenyl
RR or SS 1,2-dibromo-1,2-diphenylethane gives
trans 1,2-diphenyl
Abstracted proton and leaving group should
align trans-diaxial to be anti periplanar
(app) in approaching transition state
Equatorial groups are not in proper
alignment
KOH
Alcohol
Solvent
H
Br
H
H
H
C CH
3
CH
3
CH
3
C
H
CH
3
CH
3
CH
3
H
H
This is the cis isomer. The trans isomer does not
react by an E2 reaction.
KOH
ethanol
heat
(E)-isomer (Z)-isomer
???
???
C C
Br
H
CH
3
CH
3
H
C C
CH
3
CH
3
H t-butyl
C C
H
CH
3
CH
3
t-butyl
t-butyl
(E)-isomer
C C
CH
3
CH
3
H T-butyl
This one is formed!
KOH
ethanol
heat
(E)-isomer (Z)-isomer
???
???
C C
Br
H
H
CH
3
CH
3
t-butyl
C C
CH
3
CH
3
H T-butyl
C C
H
CH
3
CH
3
t-butyl
(Z)-isomer
C C
H
CH
3
CH
3
t-butyl
This one is formed!
Substitute deuterium for hydrogen at o
position
Effect on rate is kinetic isotope effect (k
H
/k
D
=
deuterium isotope effect)
Rate is reduced in E2 reaction
Heavier isotope bond is slower to break
Shows C-H bond is broken in or before rate-
limiting step
Competes with S
N
1 and E2 at 3 centers
V = k [RX]
E1 is not stereospecific and there is no
requirement for alignment
Product has Zaitsev orientation because
step that controls product is loss of proton
after formation of carbocation
Strong base is needed for E
2
but not for E
1
E
2
is stereospecifc, E
1
is not
E
1
gives Zaitsev orientation
Acid assisted reactions are always E1
strong acid
+
H
2
O
R C C R
R
OH
H
R
C C
R
R R
R
1)
2)
3)
+ H
+
+
+
slow
+
+ H
2
O
+
+ H
+
CH
3
C CH
3
CH
3
OH
CH
3
C CH
3
CH
3
OH
2
CH
3
C CH
3
CH
3
OH
2
CH
3
C CH
3
CH
3
CH
3
C CH
3
CH
3
C CH
2
CH
3
CH
3
85% H
3
PO
4
80 C
H H
+
C
:
H
CH
+
_
:
:
H
secondary carbocation
CH
3
C CH CH
3
CH
3
CH
3
O
CH
3
C
CH
3
CH
3
O
CH
3
CH
3
C
CH
3
CH
3
H
2
O
CH
3
+
+
major
minor
trace
CH
3
C C CH
3
CH
3
CH
3
H
CH
3
C CH CH
2
CH
3
CH
3
CH
3
C C CH
3
CH
3
H CH
3
CH
2
C CH
CH
3
CH
3
CH
3
C C
CH
3
CH
3
CH
3
CH
3
tertiary carbocation secondary carbocation
This give the anti-Zaitsev product (least
substituted product is formed)!
+
OH
_
heat
+
6%
94%
o |
|
CH
3
CH
2
CH
2
CH CH
3
N
CH
3
CH
3
CH
3
CH
3
CH
2
CH CH CH
3
CH
3
CH
2
CH
2
CH CH
2
In bimolecular elimination reactions in the
presence of either a bulky leaving group or a
bulky base, the hydrogen that is lost will come
from the LEAST highly-branched |-carbon.

|
o
|
C C C C
H
H
H H
X
H
H
H
H
CH
3
Less branched
More branched
C
C
C
H
H
H
H
CH
3
H
H
C
H
Non-bulky bases, such as hydroxide and
ethoxide, give Zaitsev products.

Bulky bases, such as potassium tert-
butoxide, give larger amounts of the least
substituted alkene (Hoffmann) than with
simple bases.
CH
3
C CH CH
3
Br
NaOC
2
H
5

C
2
H
5
OH
heat
C
CH
CH
3 CH
3
CH
3
C
CH
CH
3
Br
KOC(CH
3
)
3

(CH
3
)
3
COH
heat
C
CH
CH
3
CH
2
Major
H
CH
3
CH
3
CH
3
H
CH
3
Major
H
H
3
C CH
2
CH
2
CH
2
Br
KOCH
3
Non-bulky
S
N
2
H
3
C CH
2
CH
2
CH
2
O-CH
3
H
3
C CH
2
CH CH
2
bulky base
KO-t-butyl
E2
..
_
..
:
..
..
fast
..
_
1)
2)
..
_
slow
+ Br
_
C
O
C
O
C
O
C
O
C C
Br
C C
Br
H
H O
C C
Br
H O H
C C
These unusual reactions occur with one
carbon compounds, only.
Examples include chloroform and methylene
chloride.
Cyclopropane compounds are formed.
This reaction requires the two Brs to be
anti.
+ Zn
CH
3
COOH
+ ZnBr
2
CH
3
C CH CH
3
CH
3
Br
Br
C C
CH
3
CH
3
H
CH
3
KOH
ethanol
NaNH
2
NaNH
2
R C C R
Br
H
Br
H
C C
R
H R
Br
C C R R
R C C R
Br
H
Br
H
C C R R
Alkyl halides undergo different reactions in
competition, depending on the reacting
molecule and the conditions
Based on patterns, we can predict likely
outcomes.
Minggu-ke-13
Involves several simultaneous bond-making
breaking process with a cyclic transition state
involving delocalized electrons
The combination of steps is called a concerted
process where intermediates are skipped
Pericylic reactions is a type of concerted organic reaction which
occurs through cyclic transition state in order to maintain electron
flow. They are usually rearrangement reactions.
Pericylic Reactions are listed below:
1. Electrocylic Reactions
2. Cycloadditions
3. Sigmatropic Reactions
Woodward-Hoffman rules are set of rules in organic chemistry
predicting the stereochemistry of pericyclic reactions based on orbital
symmetry.

These are pericyclic processes that involves the
cyclization of a conjugated polyene
One t bond is broken, the other t bonds
change position, a new bond is formed, and a
cyclic compound results
Gives specific stereoisomeric outcomes related
to the stereochemistry and orbitals of the
reactants
A o-bonded substituent atom or group
migrates across a p electron system from one
position to another
A o bond is broken in the reactant, the p bonds
move, and a new s bond is formed in the
product
Sigmatropic reaction is a pericyclic reaction involves the migration
of sigma bond from one site to another site in the same molecule.

over pi-bonded system
governed by orbital
symmetry
concerted
intramolecular
rearrangement
uncatalyzed
classified due to moving substituent that is given [i,j],
format i and j number of the atoms that each sigma bond
moved. Generally; [1,n] and [n,m]
mostly
hydrogen
shifts
from one end
(1) to another
end (n)
Stereochemistry of [1,n] Sigmatropic RAR
Supra
H moves same
face of the n-
plane
3
4
5
H
1
2
H
[1,5] sigmatropic
6 electrons
(4n+2)

Antra
H moves
opposite of the
n-plane
Stereochemistry of [1,n] Sigmatropic RAR
4 3
5
6
7
2
1
H
H
[1,7] sigmatropic
8 electrons
(4n)

Stereochemistry of [1,n] Sigmatropic RAR
[i,j] Thermal Excited State (hv)
[1,3] Antra Supra
[1,5] Supra Antra
[1,7] Antra Supra
4n+2, supra, retention, Thermal, allowed
[1,2] 2-electron system (4n+2)
[1,3] 4-electron system (4n)
[1,5] 6-electron system (4n+2)
[1,7] 8-electron system (4n)
sigma bond
moves
chairlike or
boatlike transition
state

Stereochemistry of [n,m] Sigmatropic RAR
Chairlike
[3,3] Sigmatropic
6 electrons
Stereochemistry of [n,m] Sigmatropic RAR
Boatlike
Cope RAR
10-electron system
[2,3] 6-electron system (Wittig RAR)
(Claisen RAR) [3,3] 6-electron system
Numbers in brackets refer to the two
groups connected by the s bond and
designate the positions in those groups to
which migration occurs
In a [1,5] sigmatropic rearrangement of a
diene migration occurs to position 1 of the
H group (the only possibility) and to
position 5 of the pentadienyl group
In a [3,3] Claisen rearrangement migration
occurs to position 3 of the allyl group and
also to position 3 of the vinylic ether
A [1,5] sigmatropic rearrangement involves
three electron pairs (two t bonds and one o
bond)
Orbital-symmetry rules predict a suprafacial
reaction
5-methylcyclopentadiene rapidly rearranges at
room temperature
Cope rearrangement of 1,5-hexadiene
Claisen rearrangement of an allyl aryl ether
Diels-Alder reaction
Creates two new C-C bonds
Forms a cyclic molecule



Reactants are:
Conjugated diene
Alkene (dienophile) - diene loving
MUST have electron-withdrawing group!!!
Dienophiles
EWG increases the reactivity by sucking electron
density from the alkene






Remember: Conjugated Diene is Nucleophilic
Mechanism
Similar to a 1,4-addition to butadiene




Reaction is concerted to form new bonds
EWG
+
EWG EWG
4t 2t
[4+2] cycloaddition
The reaction is
concerted - all
of the orbitals
are aligned in a
6-ring.
DIELS-ALDER REACTION
HOMO
LUMO
R
push
W
pull
The HOMO
of the diene
donates elec-
trons into the
LUMO of the
dienophile.
(diene)
(dienophile)
1
2
173
The reaction is stereospecific,
maintaining relative
relationships from reactant to
product
There is a one-to-one
relationship between
stereoisomeric reactants and
products
Reactants align to produce endo (rather
than exo) product
endo and exo indicate relative
stereochemistry in bicyclic structures
Substituent on one bridge is exo if it is anti
(trans) to the larger of the other two
bridges and endo if it is syn (cis) to the
larger of the other two bridges
If the two bridges are equal, the product
with the substituent endo to the new
double bond is formed.
The relative positions of the two double
bonds in the diene are the cis or trans
two each other about the single bond
(being in a plane maximizes overlap)
These conformations are called s-cis and
s-trans (s stands for single bond)
Dienes react in the s-cis conformation in
the Diels-Alder reaction