O’Neil
Organic Reactions
Winter 2013
Chemistry 425b: Organic Reactions
Dr. Gregory O’Neil
Department of Chemistry
Western Washington University
1 O’Neil
Organic Reactions
Winter 2013
-
Meyers, A. “Chemistry 215 Handouts,” available at:
http://www.chem.harvard.edu/groups/myers/page8/pag
e8.html
Preface
This text/workbook was designed to accompany a onequarter
advanced
undergraduate
chemistry
elective.
Presentations of topics are by no means a complete treatise on
the subject. Rather, these provide an entry point to core
principles governing organic reactions. Selected examples are
given to highlight these reactions in the context of complex
molecule synthesis. An effort has been made to provide students
with references that encourage further reading on a given topic.
The text is divided roughly into two halves (see Table of
Contents), beginning with a more detailed analysis of reactions
that should be familiar to students that have completed
sophomore organic chemistry. Topics discussed include FMO- and
conformational analysis. This then is followed by more synthesisoriented subjects including fundamental reactions like oxidations
and reductions plus more specialized topics like selectivity
models for carbonyl additions and methods for alkene synthesis.
It is the intention of the author to supplement this text with
information on special topics that include protecting groups and
palladium-catalyzed cross-coupling reactions.
Significant inspiration was gained from the following
sources:
-
-
Boger, D. “Modern Organic Synthesis, Lecture Notes,”
TSRI Press, La Jolla, CA.
Evans, D. “Chemistry 206: Advanced Organic Chemistry,”
available at:
http://isites.harvard.edu/icb/icb.do?keyword=k7863
Phillips, A. “Chem 5311, Advanced Synthetic Organic
Chemistry I”, Univ. Colorado, Boulder, 2006.
Gregory O’Neil, November 29,2012.
Table of Contents
Chapter
Page
1. Principles of Organic Reactions
3
2. Conformational Analysis
18
3. Kinetics and Thermodynamics
24
4. Pericyclic Reactions
31
5. Oxidation Reactions
46
6. Reactions at the Carbonyl
56
7. Alkene Synthesis
71
8. Alkene Metathesis
77
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Organic Reactions
Ch. 1 What do we need to know to understand,
predict, and design organic reactions?
Methodology: An organic chemist’s toolkit.
Retrosynthesis: A strategy for analyzing complex problems.
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Classes of Mechanisms
Three general types:
a) Polar
Movement of PAIRED electrons
Mechanism: A framework for predicting and understanding the
products and stereochemistry of a reaction
Mechanism Basics
Notation:
b) Free radical
Movement of UNPAIRED electrons
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Organic Reactions
c) Pericyclic
Movement of electrons within a closed ring (there are no
intermediates, ions or radical species)
Universal Effects Governing Chemical Reactions:

Steric Effects – Nonbonding interactions (Van Der Waals
repulsion) between substituents within a molecule or
between reacting molecules.

Electronic Effects (Inductive Effects) – The effect of
bond and through-space polarization by heteroatom
substituents on reaction rates and selectivities.
Pericyclic reactions can be subdivided into 4 categories:
i.
ii.
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Cycloadditions
Electrocyclic Reactions
Rate decreases as R becomes more electronegative
iii.
Sigmatropic rearrangements
iv.
Group Transfer reactions

Stereoelectronic Effects – Geometrical constraints
placed upon ground and transition states by orbital
overlap considerations.
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Organic Reactions
Steric vs. Electronic Effects: Case studies when steric and
electronic effects lead to differing stereochemical outcomes:
Woerpel et al., J. Am. Chem. Soc. 1999, 121, 12208
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MO Theory: The H2 Molecule (revisited)
Let’s combine two hydrogen atoms to form H2.

Rule 1: A linear combination of n atomic orbitals (AOs)
will create n Molecular Orbitals (MOs).
O
(Bu)2CuLi
O
EtO2C
Bu
EtO2C
OR
What happens when you add two electrons to the MO diagram
above? How about four electrons?
O
OR
EtO2C
Bu3Al

O
Bu
EtO2C
Bu
Bu
Al
OR
Bu
Yakura et al., Tetrahedron 2000, 56, 7715
OR
Rule 2: Each MO is constructed by taking a linear
combination of the individual atomic orbitals:
Bonding MO
σ = C1ψ1 + C2 ψ2
Antibonding MO
σ* = (C1*)ψ1 + (C2*) ψ2
The coefficients C1 and C2 represent the contribution of
each AO.
The squares of the C-values are a measure of the electron
density on the atoms in question.
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
Organic Reactions
Rule 3: Both wave functions must contribute one net
orbital.
Consider the C-O pi-bond of acetone.
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Chemical Bonding

Bond strengths (Bond Dissociation Energies) are composed
of a covalent (δ Ecov) and ionic contribution ((δ Ecov).

As two molecules collide:
a) The occupied orbitals of one molecule repel the
occupied orbitals of the other.
b) Any positive charge on one attracts negative
charge on the other.
c) The occupied orbitals of each interact with the
unoccupied orbitals of the other.
Overlap between orbitals is most effective for orbitals of
similar size and energy (Frontier Molecular Orbital Theory).
In the ground state, pi C-O is polarized toward oxygen.
Note that the antibonding orbital is polarized in the
opposite direction (Rule 3)
What does this mean in terms of reactivity?
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
Organic Reactions
Consider Group IV elements Carbon and Silicon:
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Case 1: Anti nonbonding electron pair and C-X bond.
Compare anti (favored) vs. syn (disfavored) E2 eliminations.
Case 2: Two anti sigma bonds.
Weak bonds have corresponding low-lying antibonding orbitals.

Orbital orientation greatly affects the strength of the
interaction.
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
The interaction of a vicinal bonding orbital with a porbital is referred to as hyperconjugation.
Donor Acceptor Properties
Consider the energy levels for both bonding and antibonding
orbitals:
Stereoelectronic requirement: Syn-planar orientation between
interacting orbitals.
MO Description:
 C-R
H
H
The greater electronegativity of oxygen lowers both the bonding
and antibonding C-O states. Hence:
H
H
 C-R
σ C-C is a better donor orbital that σ C-O
σ* C-O is a better acceptor orbital than σ* C-C

Hierarchy of Donor Acceptors:
The new occupied orbital is lower in energy. When you stabilize
the electrons in a system, you stabilize the system as a whole.
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
Organic Reactions
Consider the following X-ray structures of adamantine.

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Delocalization of nonbonding electrons into vicinal
antibonding orbitals is also possible.
Bonds participating in hyperconjugation (e.g C-R) will be
lengthened while the C(+)-C bond will be shortened.
M.O Description
T. Laube, Angew. Chem. I. E. 1986, 25, 349.
As the antibonding C-Y orbital energy decreases, the magnitude
of this interaction will increase.
Note that σ C-Y is slightly destabilized.
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
Organic Reactions
Since nonbonding electrons prefer hybrid orbitals, this
orbital can adopt either a syn or anti to the vicinal C-Y
bond.
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Example: N2F2
This molecule can exist as either cis or trans. Which is preferred?
Syn Orientation
Orbital Interactions:
M.O Description
Anti Orientation
Electrostatic Interactions (Dipole)?
Overlap is better in the anti orientation.
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Organic Reactions
Anomeric Effect

A methoxy substituent on a cyclohexane ring prefers to adopt
the equatorial conformation.
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Other electronegative atoms such as Cl, SR, etc. also
participate in anomeric stabilization.
Why is the axial C-Cl bond longer?
Whereas the closely related 2-methoxytetrahydropyran prefers
the axial conformation.

There is also a rotational bias on the exocyclic C-OR
bond.
The effect that provides the stabilization which overrides the
inherent steric bias is referred to as the anomeric effect.
Principle HOMO-LUMO interaction:
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
Organic Reactions
Spectroscopic Evidence
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Rationalize why B is more stable than A.
Can you explain the following IR trends?
Katritsky, J. Chem. Soc. B 1970, 135.
Compare the C-H stretching frequency for an aldehyde and
related alkene.
Carboxylic Acids and Esters

Conformations: There are two planar conformations.
Specific Case: Methyl Formate.
The N-H stretching frequency of cis-methyl diazene is 200 cm-1
lower than the trans isomer.
Me
H
N
N
 N-H = 2188 cm-1
Me
N
N
H
 N-H = 2317 cm-1
The (E) conformation of both acids and esters is less stable by 35 kcal/mol. Sterics would predict that the (E) conformer of
methyl formate would be preferred (H smaller than O). Since
this is not the case, electronics must be considered.
N.C Craig & coworkers J. Am. Chem. Soc. 1979, 101, 2480.
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
Organic Reactions
Conjugation and Hybridization
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Esters vs. Lactones
Note that the alkyl oxygen is sp2 hybridized in order to allow for
conjugation (resonance).
Esters prefer to adopt the (Z) conformation while small ring
lactones are constrained in the (E) conformation. Explain the
following:
1. Lactone 2 is significantly more susceptible to nucleophilic
attack at the carbonyl carbon than 1.
2. The pKa of 2 is 25 while ester 1 is 30.

Reactions
 Peracid epoxidation of alkenes.
Hyperconjugation
(Z) Conformer:
Identify the important orbital interactions.
(E) Conformer:
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Organic Reactions
How important is the trajectory of approach for
reacting molecules?
Baeyer-Villiger reaction.

Can you rationalize the rate date below? (Hint: Why is that the
preferred intermediate?)
O
kR
R
O
C
R
Me
O
R
C
+
Me
CF3CO3H
R
RS
sp3 hybridized: SN2 displacement.
kR / kMe
CH3CH2
72
(CH3)2CH
150
(CH3)3C
830
C
O
Me
OH
O
RL

O
kMe
via
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CF3
O
where RL = large substituent
RS = small substituent
O

Tether Nu and X
Eschenmoser Helv. Chim. Acta 1970, 53, 2059.
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O
O
S
O
O
CH3
S
Nu:
Nu
O
sp2 Hybridized: C=O and C=C.
Some history:
O
CH3
OMe
OMe
OMe
OMe
O
O
S
H C H
Nu
H
N
not 180°
sealed tube, 48 h
har sh
O
O

SO3CH3
+
(CH3)3N
NH2-OH
SO3-
HO
X
exclusively
intramolecular
X
Me N
Me
H
H
C
S
O
I
O
N
O
O
H
Perkin J. Chem. Soc. 1916, 109, 815.
1. Led to the idea of a partial through-space bond between
Nitrogen and the carbonyl.
2. Later, Brent proposed that X-ray structures of donoracceptor systems might represent the early stages of
chemical reactions. (Chem. Rev. 1968, 68, 587)
O
Beak Acc. Chem. Res. 1992, 25, 215.
OMe
N
O
O
King et al. Tet. Lett. 1982, 23, 4465.
N
O
OMe
Endocyclic Restriction Test
(CH3)2N
O
MeI, MeOH
intramolecular not possible
O
X

O
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N
Burgi J. Am. Chem. Soc. 1973, 9515 5065.
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Organic Reactions
Required Trajectories: Summary Winter 2013
B. Endo-cyclization – The bond that is breaking is endocyclic to
the forming ring.
Baldwin J. Chem. Soc., Chem. Commun. 1976, 734.
C. Ring Closures are classified according to hybridization of the
electrophilic component and size of the ring formed. Examples:
Baldwin’s Rules: Stereoelectronic Considerations for
Ring-Closure.
Baldwin’s Rules provide a qualitative set of generalizations on
the probability of a given ring-closure.
They do not apply to non-first-row elements or electrocyclic
processes.
 Nomenclature:
A. Exo-cyclization – The bond that is breaking is exocyclic to the
forming ring.
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Most exo cyclizations are allowed.
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Case 2:
Example: Formation of 3-membered rings:
Some endo cyclizations are disallowed.
Case 1:
Case 3:
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Conclusions
3
4
5
6
7
Tet





EXO
Trig





Dig
X
X



Tet
X
X
X
ENDO
Trig
X
X
X


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The eclipsed conformer may be broken down into its individual
destabilizing interactions.
Dig





Further reading:
Structure
Eclipsed Atoms
ΔE (kcal mol-1)
Ethane
H
H
1.0
Propane
H
H
H
CH3
1.0
1.4
FMO Analysis:
Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
Ch. 2 Conformational Analysis
Reviews: Hoffmann, R. W. Angew. Chem. I. E. 2000, 39, 2054
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841
Ethane and Propane
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Butane
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Pentane
Me
H
Me
H
H
H
H
H
H
H Me
Me
staggered
eclipsed
E=?
Torsional Energy Diagram
Heirarchy of Me – Me Interactions
Can you calculate the magnitude of the Me
H3C
ca 3.1
– Me interaction?
CH3
CH3
3.7
CH3
CH3
CH3
CH3
CH3
3.9
~7.6
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Organic Reactions
Consider the conformation of zincophorin: Winter 2013
Propylene (Propene) Torsional Strain:
Can you identify the lowest/highest energy conformations?
Allylic Strain: Propane vs. Propene
3-methyl-1-butene
2-Z-butene
Hybridization changes the C-C-C bond angle.
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Can the following selectivity: Winter 2013
Amides
J. Am. Chem. Soc. 1979, 101, 259.
This has important consequences for the enolate chemistry of
amides:
Allylic Strain: Definition
Ketones and Aldehydes
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Can you predict the stereochemical outcome of this reaction?
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Cyclohexane
Cyclic Systems
A chair ring-flip interconverts axial and equatorial substituents:
Strain Energy and Ring Size
Substituted Cyclohexanes:
10
kcal/mol
8
Methylcyclohexane
6
4
2
0
3
4
5
6
7
8
Ring Size
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Typical A Values (kcal/mol):
FG
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Stereoselective Reductions:
A Value
FG
A Value
F
0.25
OEt
0.9
Cl
0.6
CO2Et
1.15
Br
0.5
NH2
1.4
I
0.5
CH3
1.8
OH (in C6H6)
0.7
CH2CH3
1.9
OH (in i-PrOH)
0.9
CH(CH3)2
2.1
OCH3
0.75
C(CH3)3
4.9
Six-Membered Rings with Heteroatoms
Note the difference between iPr and tBu A Values.
Consider the following A-Values:
Consider 3-methylcyclohexanone:
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Organic Reactions
Note on axial vs. equatorial interconversion:
To achieve a high ratio of products in a thermodynamically
controlled reaction, you need the following ΔG’s (kcal/mol):

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A values are additive
K (25 °C)
ΔG
K (0 °C)
2 (67:33)
0.41
2.1 (68:32) 0.41
2.9 (75:25) 0.41
5 (83:17)
0.95
5.7 (85:15) 0.95
11.6 (92:8) 0.95
9 (90:10)
1.30
10.9 (92:18) 1.30
28.5 (97:3) 1.30
20 (95:5)
1.74
27.5 (96:4) 1.80
103.3 (99:1) 1.80
ΔG
K (-78 °C)
ΔG
Consider the following hydrogenation reaction:

Even though Cl has a very small A value, the energy of
activation (Ea) is high (it must go through a half-chair
conformation).
Ch. 3 Kinetics and Thermodynamics of Organic
Reactions
Overall this reaction is exothermic (ΔG = -17 kcal/mol), so the
reaction is favorable or spontaneous.
An equilibrium can be described by:

But experimentally this reaction is very slow, it takes
about 2 x 104 years to hydrogenate one mole of ethylene
(without a catalyst).
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Kinetic vs. Thermodynamic Control
A transition state (TS) possesses a defined geometry and charge
delocalization but has no finite existence.
If this is an irreversible reaction, the major product will be B. If
the reaction is reversible, C will be major (more stable product).
Intra- versus Intermolecular Reactions
Hammond Postulate
The transition state most closely resembles the side (i.e reactant
or product) to which it is closer in energy.
Consider the solvolysis of tert-butyl chloride: Step 1:
CH3
H3C
MeOH
Cl
CH3

Intramolecular reactions have a far more favorable entropy of
activation.
Step 2:
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The transition states will resemble the geometry of the
carbocation intermediate and not the reactant or product.
Conformational Effects on Reactivity

Ester Hydrolysis

Oxidation
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
Organic Reactions

Substitution Reactions
Which of the following SN2 reactions is faster?
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Elimination Reactions
Can you explain the following ratio of elimination products?
Consider the E2 Elimination of:
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Organic Reactions
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
Epoxide Opening
Under kinetically controlled conditions (irreversible), product
ratios are dependent on Ea (ΔΔG‡).
Consider the following:
path (a)
CH3
path (b)
CH3 SPh
CH3
(b)
O
O
H
O-
H
(a)
H
twist boat
conformation
1,3-diaxial
exclusive pr oduct
SPh
H

Epoxide Opening
CH3
SPh
CH3
H
OH
H
CH3
HO
PhS
H
less stable product
O-
H
chair conformation
H
H
more stable product
Atom under attack moves toward the nucleophile.
Reactions that proceed via a ground state conformation are
typically faster.
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
Organic Reactions
Rearrangements
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From the previous example, how does the rate of conformer
intercoversion effect the product distribution?
There are two limiting cases to consider:
a) The rate of reaction is much faster than interconversion
i.e k3,k4 >> k1,k2
b) The rate of reaction is much slower than interconversion
i.e k3,k4 << k1,k2
Case A: The two conformers cannot equilibrate during the
reaction. The product ratio thus depends solely on the initial
ratios of the two conformers (aka “Kinetic Quench”).
Case B: The two conformers can equilibrate during the reaction.
The product ratio depends on the difference in activation
energies (Ea) leading to the respective products (“CurtinHammett conditions”).
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Ch. 4 Pericyclic Reactions Winter 2013
Some things to consider:

A pericyclic reaction is characterized as a change in
bonding relationships that takes place as a continuous,
concerted reorganization of electrons.

The term "concerted" specifies that there is one single
transition state and therefore no intermediates are
involved in the process. To maintain continuous electron
flow, pericyclic reactions occur through cyclic transition
states.
a. The number of electrons involved is important.

More precisely: The cyclic transition state must
correspond to an arrangement of the participating
orbitals which has to maintain a bonding interaction
between the reaction components throughout the course
of the reaction.
b. Pericyclic reactions are stereospecific
Is it possible to predict the stereochemical outcome of this
reaction?
c. Reactions
behave
differently under
conditions (i.e thermo- vs. photochemical)
different
Huisgen Tet. Lett. 1964, 3381.
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We can explain and predict the outcome of pericyclic reactions
using Frontier Molecular Orbital (FMO) theory (HOMO and LUMO
interactions) and orbital symmetry. Winter 2013
Disrotatory Closure:
For further reading see:
Woodward, Hoffmann, The Conservation of Orbital Symmetry,
Academic: New York, 1970.
Fleming, Frontier Orbitals and Organic Chemical Reactions,
John-Wiley and Sons, New York, 1976.
Some Observations 
butadienes undergo conrotatory closure under thermal
conditions

hexatrienes undergo disrotatory closure under thermal
conditions.
Fukui, Acc. Chem. Res. 1971, 4, 57.; Angew. Chem. I. E. 1982,
21, 801.
Some Classes of Pericyclic Reactions
1. Electrocyclic Ring Closure/Opening
Ring closure (and hence opening) can occur in two distinct ways:
Conrotatory Closure:
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
Organic Reactions
Under photochemical conditions 4 electron systems
undergo disrotatory motion
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FMO Analysis Butadiene π Molecular Orbital Diagram:

while 6 electron systems undergo conrotatory motion.
conrotation

4 π electron thermal reaction
h
Me
Me
Me
Me 32 O’Neil

Organic Reactions

6 π electron thermal reaction
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4 π electron photochemical reaction
Overall:
No. π electrons
4n (n = 0,1…)
4n + 2
Thermal
conrotatory
disrotatory
hν
disrotatory
conrotatory
Photochemical Activation:
When light is used to initiate an electrocyclic rxn, an electron is
excited from Ψ2 to Ψ3. Treating Ψ3 as the HOMO now shows
that disrotatory closure is allowed and conrotatory closure is
forbidden.
2. [1,3]-Sigmatropic Rearrangements
Consider the following H-Migration:
‡
H
ion
X
Y
H
X
H
Y
X
Y
‡
H
radical
X
Y
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Organic Reactions
The hydrogen can move across the pi system in one of two ways.
If hydrogen migrates on the same side of the system, it is said to
migrate suprafacially with respect to that system. If hydrogen
migrates from one side of the pi system to the other, it is said to
migrate antarafacially.
Winter 2013
The bridging distance is too great for the antarafacial migration.
Hence, [1,3] hydrogen migrations are not observed under
thermal conditions. Under photochemical conditions, the [1,3]
rearrangement is allowed suprafacially.
How would you predict this using FMO?
What about a [1,5] Hydrogen Shift?
FMO Analysis of Hydrogen Migration:
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3. [3,3]-Sigmatropic Rearrangements
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The Cope rearrangement proceeds in a concerted manner via a
chair transition state and requires no acid or base catalysis.
Consider the following:
Me
Me
Me
Me
E
99.7%
Me
The reaction can proceed via a chair or boat transition state
Me
Z
Me
Me
Me
E
Me
E
0.3%
Can you explain the following product distribution?
Some examples of [3,3]-Sigmatropic Rearrangements:
a) Cope Rearrangement
Doering Tetrahedron 1962, 18, 67.
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
Organic Reactions
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Mechanism:
Applications
Oxy-Cope

Applications
Evans and Golob showed that the oxy-Cope rearrangement could
be greatly accelerated by deprotonation of the alcohol.
J. Am. Chem. Soc. 1975, 97, 4765.
Review: Paquette Tetrahedron 1997, 53, 13971.
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b) Claisen Rearrangement
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A general mechanism:
Review: Wipf Comprehensive Organic Synthesis 1991 Vol. 5 pp
821-871.
There are a number of important variants of this important
reaction:
Applications
Aromatic Claisen:
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Johnson Claisen:
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Ireland deprotonation model:
Ireland Claisen:
The stereochemical outcome can be controlled by careful
control of the enolization conditions.
Compare the following to the previous related Johnson Claisen. 38 O’Neil
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The chair TS may not always be accessible:
Some common cycloaddition reactions include:
4. Cycloaddition Reactions A cycloaddition reaction is the union of two smaller,
independent pi systems. Sigma bonds are created at the expense
of pi bonds.
How do we explain the following observations?
Cycloaddition reactions are referred to as [m + n] additions
when a system of m conjugated atoms combines with a system of
n conjugated atoms.
In a cycloaddition, a pi system may be attacked in one of two
distinct ways. If the pi system is attacked from the same face,
then the reaction is suprafacial on that component. If the
system is attacked from opposite faces, then the reaction is
antarafacial on that component.
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Role of FMO’s:
Winter 2013
Can you design suitable substrates for an inverse electron
demand Diels-Alder reaction?
[2+2]-Cycloaddition
Two geometries of approach can be envisioned. Consider
thermal activation:



HOMO-LUMO gap controls the rate of reaction. Smaller
gap = faster reaction.
Electron-withdrawing groups lower the energy of the
HOMO and LUMO.
Electron-donating groups raise the energy of the HOMO
and LUMO
Reactions between electron-rich dienes and electron-poor
dienophiles are referred to as normal electron demand DielsAlder reactions. The most significant orbital overlap is between
the HOMOdiene and LUMOdienophile.
For a normal electron demand process the most valuable feature
of a good dienophile is a low-energy LUMO, usually achieved by
conjugation to an electron withdrawing group.
The simplest approach (Supra/Supra) is forbidden under thermal
activation. The less obvious approach (Antara/Supra) is allowed
thermally but geometrically rather congested.
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Photolytic [2+2]-cycloadditions are quite common.
Winter 2013
a) Stereochemistry
The Diels-Alder reaction is stereospecific (i.e the relative
stereochemistry in the diene and dienophile are preserved in the
product).
Compare:
[4+2]-Cycloaddition
Normal Diels-Alder reaction under thermal activation:


Suprafactial with respect to both reaction components.
Reaction proceeds through a boat transition state.
41 O’Neil
Organic Reactions
Endo products are typically favored even though exo products
are often more stable.
Winter 2013
Because of the well-defined stereochemical and regiochemical
behavior, the Diels-Alder reaction has been used extensively in
complex molecule synthesis. Required Reading: Nicolau, Angew. Chem. I. E. 2002, 41, 1668.
see also: Tadano et al. Chem. Rev., 2005, 105, 4779.
Some examples:
b) Regiochemistry
Regiochemistry can often be predicted by considering polarity of
the reacting substrates.
42 O’Neil
Organic Reactions
Enantioselective Diels-Alder Reactions.
Winter 2013
Chiral Lewis Acid Catalyst:
One system of broad utility employs an oxaolidinone as a chiral
auxiliary.
Role of Lewis Acid:
Organocatalyst
O
Me
CHO
10 mol% cat.
H
90% ee
H2O, 0 °C
90%
cat
Ph
O
N
Me
endo
O
N
H
Macmillan JACS 2002, 122, 2458
43 O’Neil
Organic Reactions
Ch. 5 Oxidation Reactions.
Winter 2013
Organic Syntheses, Coll. Vol. 10, p.696 (2004); Vol. 77, p.141
(2000).
Alcohol Oxidations.



Good for small scale reactions.
Tolerant of a wide range of functionality.
Can buffer with pyridine or NaHCO3(s).
Some examples:
General mechanism:
O
There are a number of reagents for this purpose, this is a survey
of some of the most common reagents used in synthesis.
O
O
Dess, Martin, J. Org. Chem. 1983, 48, 4155.
Dess, Martin, J. Am. Chem. Soc. 1991, 113, 7277
HO
O
OTMS
O
Dess-Martin,
H
1. Dess-Martin Periodinane
O
OTMS
H
NaHCO3, CH2Cl2
O
O
H
OTMS
H
O
Preparation:
OTMS
Synlett, (4), 313-14; 1992
44 O’Neil
Organic Reactions
Winter 2013


Tolerant of a large range of functionality.
Basic conditions can cause electrophilic additions α to the
carbonyl or β-eliminations:
2. Swern
Swern, J. Org. Chem. 1978, 43, 2480.
Mechanism:
Some Examples:
45 O’Neil
Organic Reactions
3. Tetrapropylammonium Perruthenate (TPAP)
Winter 2013
4. TEMPO Review: de Nooy et. al Synthesis 1996, 1153.



Essentially neutral conditions.
Ruthenium is expensive, used catalytically with NMO as
the stoichiometric oxidant.
Molecular sieves are used to prevent overoxidation of
aldehydes to carboxylic acids.


Good selectivity for 1° vs. 2° alcohols.
Cheap, stoichiometric oxidant is bleach.
Mechanism (See Tetrahedron 1998, 54, 667.):
Selected Examples:
46 O’Neil
Organic Reactions
Winter 2013
Examples:
b) PCC (Tet. Lett. 1975, 2647)
-
Only slightly acidic.
Workup and removal of chromium
salts can be laborious.
N
H
O
Cr
O
Cl
O
"PCC"
Still widely used:
5. Chromium-Based Oxidations
a) Jones Reagent (J. Chem. Soc. 1953, 2548.)
- Simple Prep: 67 g. of chromium trioxide in 125 ml. of
distilled water. To this solution is added 58 ml. of
concentrated sulfuric acid and the salts which precipitate
are dissolved by addition of a minimum quantity of
distilled water; the total volume of the solution usually
does not exceed 225 ml.
- Very acidic, good for the oxidation of simple primary
alcohols to carboxylic acids or secondary alcohols to
ketones.
47 O’Neil
Organic Reactions
6. Oxidation of primary alcohols to carboxylic acids.
Winter 2013
c) Two Step:
a) TEMPO plus NaClO2 (J. Org. Chem. 1999, 64, 2564.)
- Two step cycle consisting of TEMPO oxidation to the
aldehyde followed by NaClO2 oxidation to the carboxylic
acid.
-
There are many choices for step 1.
Step 2 can be achieved using NaClO2 in the presence of a
phosphate buffer and 2-methyl-2-butene as an acid
scavenger.
b) RuCl3-NaIO4 (J. Org. Chem. 1981, 46, 3936).
- Will also oxidize alkenes.
O
Ph
OH
O
2.2 % RuCl3, NaIO4
Ph
1h, rt. 75%
CO2Me
cat. Ru, NaIO4
Ph
rt.
Ph
OH
O
Ph
CO2Me
CO2H
JACS 1996, 118, 6897.
48 O’Neil
Organic Reactions
Oxidation of Carbon-Carbon Double Bonds
Stereochemistry
Consider the following:
1. Epoxidation Reactions.


Winter 2013
Peroxyacids:
Mechanism:
Rickborn, J. Org. Chem. 1965, 30, 2212.
Singleton and Houk, J. Am. Chem. Soc. 1997, 119, 3385.
49 O’Neil
Organic Reactions
Winter 2013
Three of the following reactions are diastereoselective the
fourth is not. Explain.
There is a small difference in the energies of the products, but a
larger difference for reagent approach in the transition states.

Allylic Alcohols
Henbest, J. Chem. Soc. 1957, 1958.
Original proposal for selectivity:
50 O’Neil

Organic Reactions
Enantioselective Epoxidation: Sharpless Asymmetric
Epoxidation
Sharpless, Katsuki, J. Am. Chem. Soc. 1980, 102, 5974. Review:
Pfenniger, Synthesis 1986, 89. Sharpless Tetrahedron 1994, 50,
4253.
Winter 2013
The enantiofacial selectivity is determined by the choice of
ligand. As drawn, (-)-DET would result in epoxidation from the
top face while (+)-DET would give the epoxide on the bottom
face.
The original paper described the first truly general and useful
asymmetric reaction.
R1
R2
R3
yield
ee(%)
H
H
H
Ph
n-decyl
H
Pr
n-decyl
H
H
Me
H
H
H
Ph
15
80
82
87
79
73
89
90
95
95
3 Å or 4 Å molecular sieves are required to ensure both high
conversion and ee. A typical reaction is run with 5 mol% Ti(iPrO)4, and 6 mol% (+) or (-) tartrate ester.
Some recent examples:
51 O’Neil
Organic Reactions
Winter 2013
observation and chiral cinchona alkaloids ligands as the source of
asymmetry.
Some useful patterns of reactivity for 2,3-epoxy alcohols:
Asymmetric Dihdroxylation: Sharpless
Pthalazine (PHAL) and diphenylpyrimidine (PYR) derivatives of
DHQ/DHQD give generally higher ee and allow for the
formulation of AD-mix-α (contains (DHQ)2PHAL) and AD-mix-β
(contains (DHQD)2PHAL). These commercially available systems
contain:
(DHQ)2PHAL or (DHQD)2PHAL 0.0016 mole
Potassium carbonate, 0.4988 mole
Potassium ferricyanide 0.4988 mole (reoxidant)
Potassium osmate dihydrate 0.0007 mole (non-volatile Os(VIII))
Hentges, Sharpless J. Am. Chem. Soc. 1980, 102, 4263.
Review: Chem. Rev. 1994, 94, 2483.
The catalytic variant of an old and powerful reaction:
Criegee noted that dihydroxylation could be accelerated in
pyridine. Sharpless’ asymmetric variant builds upon this
52 O’Neil
Organic Reactions
The facial selectivity can be predicted by:
Winter 2013
Ch. 6 Reactions at the Carbonyl: Formation of C-H
and C-C Bonds. For mono-substituted alkenes, locate RL, then orient as shown.
Some examples:
Reduction with Hydride Reagents
53 O’Neil

Organic Reactions
NaBH4
LiBH4
LiAlH4
BH3
DIBAL-H
RCHO





R2CO







Nucleophilic Hydride Reagents
a) Sodium Borohydride, NaBH4: Most commonly used in
MeOH to reduce ketones and aldehydes.
b) Lithium Borohydride, LiBH4: In THF or Et2O the increased
Lewis acidity of Li+ vs. Na+ makes this a more powerful
reductant that NaBH4. Can reduce some esters and
lactones, commonly used to cleave oxazolidinone
auxiliaries.
c) Lithium Aluminum Hydride, LiAlH4: Powerful hydride
reagent that reduces essentially all carbonyl groups as
well as other functional groups.
d) Lithium tri(sec-butyl)borohydride, Li(s-Bu)3BH: Bulky
hydride that is valued for increased stereoselectivity.
e) Sodium Cyanoborohydride, NaCNBH3: Stable in acid
(pH=3), primarily used to reduce imines (as part of the
reductive amination process).

Winter 2013
RCO2R
RCO2H

RCONR’2

RCN

alkene
Some Examples: 


Electrophilic Hydride Reagents
a) Borane, BH3: Most commonly as the THF- or Me2Scomplex. Used to reduce amides and acids, but will also
react with olefins and several other functional groups.
b) Diisobutylaluminum Hydride, DIBAL-H): The reagent of
choice for the reduction of nitriles to aldehyde (via the
imine), lactones to lactols, some esters to aldehydes, and
α,β-unsaturated esters to allylic alcohols.
54 O’Neil
Organic Reactions
Cyclic Ketones
Winter 2013
Enantioselective Ketone Reductions
Review: Itsuno, S. Org. React. 1998, 52, 395.

reagent
axial
equitorial
NaBH4
LiAlH4
L-Selectride
14
10
96.5
86
90
3.5
Chlorodiisopinocampheylborane, (−)-Ipc2BCl, DIP-Cl
Probably the most widely used of the many reagents for this
purpose. Particularly useful for aryl/methyl ketones.
Mechanism:
SMALL reagents prefer axial attack while LARGE reagents prefer
equatorial attack.
These reactions are under kinetic control:
Example:
Org. Process Res. Dev., 2010, 14, 193–198.
55 O’Neil
Organic Reactions
Oxazaborolidines: Itsuno-Corey System (“CBS” Reduction)
Organolithium, Grignard, and Organocopper Reagents: Hard
vs. Soft Nucleophiles
Corey, E. J. Angew. Chem. I. E. 1998, 37, 1986.
We saw previously that according to Frontier Molecular Orbital
Theory, the most important interactions are between the HOMO
of a numcleophile and the LUMO of an electrophile.
A broadly useful catalytic enantioselective reducing system.
-
Corey, E. J. et al. J. Am. Chem. Soc. 1969, 91, 5675.
N
B
H Ph
Ph
BH3-THF
N
O
H3B
O
O
OBH2
RL
RS
H Ph
Ph
N
H2B
H
RL
B
Me
Me
H
RL
B
H Ph
Ph
O
N
H2B
O
H
RS
Hard nucleophiles are characterized by a relatively lowenergy HOMO. These react fastest with hard
electrophiles which have high-energy LUMO’S. The large
separation between the HOMO and LUMO makes these
interactions more coulombic in nature and therefore
typically involve charged species.
Soft nucleophiles in contrast have a relatively highenergy HOMO. These react with soft electrophiles that
have low-energy LUMO’s. Reactions of this type are
therefore governed primarily by orbital overlap
considerations.
Example:
Catalytic Cycle:
H Ph
Ph
Winter 2013
RL
B
RS
The hydroxide ion is a hard nucleophile, because it has a charge,
and because oxygen is a small, electronegative element.
Accordingly, it reacts faster with a hard electrophile like a
proton than with a soft electrophile like bromine. However, an
alkene is a soft nucleophile, because it is uncharged and has a
high-energy HOMO. Thus it reacts faster with a soft electrohile
like bromine which has a low-energy LUMO.
HO-
+
H+
is faster than
H2C=CH2
+
H+
is slower than
HO-
+
Br Br
O
H2C=CH2
+
Br Br
O
RS
56 O’Neil
Organic Reactions
Hard vs. Soft (contd.)
Winter 2013
Example:
1,4-Addition Mechanism:
2. Organocopper Reagents - Organolithium + Copper(I) salt:
If “R” is precious (note that only one R group gets transferred to
the substrate) one can prepare “mixed” higher-order cuprates
that utilize a non-transferable or “dummy” ligand (e.g CN or 2thiophenyl):
Reagent Synthesis
1. Organolithium and Grignard Reagents
- Halide + Metal0 (most common):
-
Metal-Halogen Exchange:
57 O’Neil
Organic Reactions
Example:
Winter 2013
Review: Knochel, Chem. Rev. 1993, 93, 2117.
Enantioselective Organozinc Additions:
Review: Pu. L.; Yu, H.-B. Chem. Rev. 2001, 101, 757
Initial Report:
Some other organometallics to consider:

Organochromium Reagents
Review: Fürstner, Chem. Rev. 1999, 99, 991.
More recently:
Many examples in complex molecule synthesis:
See also Halichondrin: J. Am. Chem. Soc. 1992, 114, 3162.

Organozinc Reagents
58 O’Neil
Organic Reactions
Alkyne Additions:
Winter 2013
Diastereoselective Additions at CO.

Cram proposed the earliest model to account for the
diastereoselectivity obtained upon addition to a carbonyl
group that contains a stereocente at the α-carbon.
•
90° approach of Nucleophile
•
activated carbonyl is the
largest group
•
doesn’t consider torsional
interactions between R and RL
Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828.

Note: Carreira system reported to give no product.
How can you explain the result with no chiral ligand? And that
the stereoselection is opposite for the following:
O
OBn
OH
Et2Zn, Ti(i-PrO)4
OBn
OH
OBn
Cornforth introduced a model to account for the
stereochemistry observed with α-chloroketones. Recently
supported both experimentally and theoretically for
additions of enolboranes to α-alkoxy-aldehydes.
•
90° approach of Nucleophile
•
activated carbonyl is the
largest group
•
net dipole is minimized
+
TMS
TMS
TMS
MAJOR
Cornforth, J.W.; Cornforth, R. H.; Mathew, K. K.; J. Chem. Soc.
1959, 112;
Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem. I. E. 2003,
42, 1761
59 O’Neil
Organic Reactions
Karabatsos introduced an alternative predictive model where the
CO group eclipses either the C-RL bond or the C-RM bond

Winter 2013
Felkin-Ahn Model:
RM
O
RL
Nu
RS
•
•
•
90° approach of Nucleophile
activated carbonyl is the largest group
product ratio is determined by theinteraction of RM and O
vs RL and O
Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367

Felkin Noted that these models do not explain the effect
of the R-group on selectivity
•
90° approach of Nucleophile
•
first model to consider
torsional effects
R
Anh and Eisenstein computationally studied various conformation
preferences and added:
RM
O
RL
Nu R
S
R
Felkin-Anh
Model
•
Burgi-Dunitz trajectory of
attack
•
places the best acceptor σ*
(usually the large group)
perpendicular to attack
Anh, N.T.; Eisenstein, O. Tetrahedron Lett. 1976, 26, 155
The Felkin-Anh Model does not accurately explain:
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18,
2199.
60 O’Neil
Organic Reactions
In 1959, Cram proposed a model to account for the addition of
nucleophiles to α-hydroxy and α-amino compounds.
Winter 2013
Allyl Organometallic Additions
Allyl organometallic reagents can react in one of two ways.
Consider the following:
•
•
Chelation of the metal favors
attack from one face of the
carbonyl
Chelation control can be
extended to
Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959 81, 2748
Most reagents give predominantly the γ-addition product via two
different mechanisms:
a) For M = B, Ti, or Cr; The reaction proceeds via a “closed
transition state”:
61 O’Neil
Organic Reactions
b) For M = Si or Sn, the reaction proceeds via an “open
transition state” under Lewis acid (LA) catalysis:
Winter 2013
E-Crotylborane reagents give anti-products via a closed T.S:
Reactions that proceed via a closed transition state are
stereospecific, meaning that E-crotylation reagents give anti
products while Z-crotylation products give syn.
Z-Crotylborane reagents give syn-products via a closed T.S:
62 O’Neil
Organic Reactions
Reactions that proceed via an open transition state give
predominantly syn products for both E and Z crotylation
reagents.
Winter 2013
Chiral Reagents: Brown Allylation and Crotylation Brown, J. Am. Chem. Soc. 1990, 112, 2389.
Allylborane:
E- and Z-crotylborane:
63 O’Neil
Organic Reactions
Winter 2013
Some recent examples:
Although the stereochemical outcome of the allylboration of
aldehydes using B-allyldiisopinocampheylborane is typically
reagent controlled, this selectivity may be challenged with
certain substrates:
How can you explain the different ratios above?
Note: Removal of the campheol byproduct can be problematic.
64 O’Neil
Organic Reactions
The Aldol Reaction: An Alternative to Crotylation for
Propionate Synthesis.
Winter 2013
Consider the following aldol reaction:
How many possible stereoisomers can be formed? What needs to
be controlled in order to select for a single stereoiosomer?
1. Enolate Geometry:
Nature’s Method:
2. Enolate Facial Selectivity:
65 O’Neil
Organic Reactions
3. Aldehyde Facial Selectivity
Winter 2013
How do we control enolate geometry? Consider a Z-enolate reacting via a closed transition state:
Recall the Ireland deprotonation model:
In general, Z-enolates give syn-propionate products while Eenolates give anti products.
-
Z-enolates:
Depending on the nature of R, one can select for E or Z using
LDA, although in practice a mixture is generally observed.
Example:
-
E-enolates:
66 O’Neil
Organic Reactions
Boron Enolates
Formation of a boron enolate occurs in two steps, activation of
the carbonyl followed by deprotonation with base:
Winter 2013
Case Study: Enantioselective Aldol Reactions using chiral
oxazolidinone auxiliaries:
What are the important orbital interactions during the activation
step?
What is the purpose of the activation step?
Evans, D. A. J. Am. Chem. Soc. 1981, 103, 2876 and 3099.
Exclusive Z-enolate formation:
Depending on the nature of the borane (BR2X) and Base one can
select for either the E or Z enolate:
R
Et
i-Pr
t-Bu
Cy2BCl, Et3N
79 : 21
97 : 3
97 : 3

Facial Selectivity:
9-BBNOTf, i-Pr2EtN
3 : 97
12 : 88
90 : 10
67 O’Neil
Organic Reactions
Winter 2013
Ch. 7 Alkene Synthesis.
Example:
1. Phosphorous-Based Methods
a) G. Wittig received the 1979 Nobel Prize in Chemistry for
“many significant contributions to Organic Chemistry.” The
Wittig reaction is arguably the most widely used alkene
synthesis protocol, due in part to its predictable selectivity:
First report: Wittig and Geissler, Liebigs Ann. 1953, 580, 44
Some Examples:
68 O’Neil
Organic Reactions
The reaction involves addition of a phosphorous ylide to an
aldehyde or ketone to generate a betaine intermediate that is in
equilibrium with the corresponding oxaphosphetane:
Winter 2013
The Wittig reaction is thought to proceed via a “puckered”
transition state.
The reaction of non-stabilized ylids to give cis-alkene products
is under kinetic control while the reaction of stabilized ylids is
under thermodynamic control.
69 O’Neil
Organic Reactions
b) Horner-Wadsworth-Emmons Reaction.
Similar to the Wittig reaction, the HWE reaction involves
phosphonate stabilized carbanions. The carbanion stabilizing
group (W) is necessary for elimination to occur. Non-stabilized
phosphonates give stable beta-hydroxyphosphonates.
Winter 2013
The electron withdrawing effects are presumed to decrease
oxephosphetane lifetime and prevent equilibration.
The HWE reaction is particularly useful for macrocyclizations:
Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem. Ber. 1958, 91, 6163.
Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Chem. Ber.
1959, 92, 2499-2505.
Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1961, 83, 1733-1738.
Z-alkenes from the HWE: Stille-Gennari Modification
2. Sulfur-Based Methods: The Julia Olefination
Still, Gennari, Tet. Lett. 1983, 24, 4405.
Classically the reaction is carried out in two steps:
Base
R
trans:cis
t-BuOK
KHMDS, 18-C-6
K2CO3, 18-C-6
KHMDS, 18-C-6
Me
Me
CH2CF3
CH2CF3
5:2
8:1
1:6
1 : 12
70 O’Neil
Organic Reactions
The mechanism for elimination is thought to proceed by first E2
elimination of the acyl group followed by single electron
reduction of a vinyl sulfone:
Winter 2013
Consider the following chemoselective elimination:
Samarium diiodide (SmI2) can be used for the elimination of
benzoyloxysulfones. This reaction involves first single-electrontransfer (SET) to the benzoyl group followed by elimination of
the sulfone: Manipulations at sulfur has led to the development of a one-step
“modified
Julia”
reaction.
These
typically
involve
phenyltetrazole (PT) or benzothiazole (BT) sulfones.
Blakemore J. Chem. Soc., Perkin Trans. 1, 2002, 2563-2585.
71 O’Neil
Organic Reactions
Installation is typically via Mitsunobu displacement of the
corresponding alcohol followed by oxidation:
Winter 2013
While understanding and predicting the stereoselectivity of a
modified Julia reaction can be challenging (see Blakemore ref.
above), some generalizations can be made:

PT-sulfones tend to be more stereoselective than BT.
Mechanism: Stereochemistry is determined upon sulfone addition to the
carbonyl.

BT-sulfones work best with α,β-unsaturated aldehydes.

Pyridine sulfones give predominantly the cis-alkene.
This is presumably the result of reversible carbonyl addition and
an inability of the anti hydroxysulfone intermediate to undergo
the Smiles rearrangement. 72 O’Neil
Organic Reactions
Ch. 8 Alkene Metathesis.
Ruthenium catalysts: most widely used metathesis catalysts
because of their relative air/moisture stability (can be handled
without special precautions) and excellent functional group
tolerance.
Olefin metathesis is one specific type of metathesis reaction:

X
+
R1
R1
R
+
RuCl2(PPh3)3
X
Y
Cl
Cl
+
-PPh3
R1
+
R
R1
R1
R
R2
R1
Alkene Metathesis
R
+
N2
Ph
RuCl2(PPh3)3
R2
R1
R1
R
+
Ph
L = PPh3
= P(i-Pr)3
= PCy3
1.
+
Ph
Ru
L
+
Enyne Metathesis
R

Y
Ph Ph
Alkyne Metathesis
R

L
Sigma bond metathesis
R

Winter 2013
2.
PCy3
PCy3
Cl
Cl
Ru
PCy3
Ph
Grubbs' 1st
Generation Catalyst
Grubbs et al. J. Am. Chem. Soc. 1992, 114, 3974. CH2
CH2 Catalyst Initiation:
Historically, olefin metathesis was used in polymer chemistry Ti,
W, Mo, and Ru catalysts with poor functional group tolerance.
F3C
F3C
Ph
CHCMe3
O
W
OEt2
ArO
Cl
F3C
F3C
Ph
O Mo
O
N
•
•
Schrock catalyst
Schrock J. Am. Chem. Soc. 1988, 110, 1423
•
Electron-donating phoshines with large cone-angles
increase catalyst activity [PCy3 > P(i-Pr)3 > PPh3].
Initiation is faster if R1 = Ar compared to CH=CPh2.
If R1 = electron-withdrawing (-COOR) or electrondonating (-OR, -SR, -NR2), initiation is much slower.
73 O’Neil
Organic Reactions
Winter 2013
Types of Alkene Metathesis:
Note that each step in a metathesis reaction is reversible.
Olef in cross-metathesis
Recent investigations suggest that a pathway involving
dissociation of one of the phosphine ligands is dominant:
R
CH2
+ H2C
R'
catalyst
R'
R
+
H2C CH2
Ring-closing metathesis
catalyst
+
H2C CH2
n
n
Ring-opening metathesis polymerization
Grubbs J. Am. Chem. Soc. 1997, 119, 3887
catalyst
n
1. Ring-Closing Metathesis (RCM)
“Caught in the act”:
RCM
H2C
Pr
CH2
Grubbs' 1
H
[M] CH2
Pr
Cl PCy3
Ru
Cl
H
Me
Me
Ph
Snapper, M.L. J. Am. Chem. Soc. 1997 119, 7157.
H2C
CH2
CH2
[M]
[M]
H2C
[M]
74 O’Neil

Organic Reactions
Winter 2013
Tetrasubstituted alkenes:
Effect of Alkene Substitution:

Effect of Ring Size: 5- ,6-, and 7-membered ring
formations are generally straightforward, however larger
rings can be challenging.
Grubbs, R. H. J. Org. Chem. 1997, 62, 7310
Reactions above performed using Grubbs’ second generation
catalyst:
There is an entropic driving force for RCM with the generation of
ethylene:
Recently there have been reports of performing metathesis
reactions under slight vacuum to remove gaseous products.
See: J. Am. Chem. Soc. 2000, 122, 58-71.
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
Organic Reactions
It is important however that this interaction not be too
strong/stable:
Conformational Requirements:
( )n
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Grubbs' I
Ru
oligomers
high dilution
Ru
O
R
O
R
diminished activity
O
O
O
O
Grubbs' I
high dilution
79%
Despite the challenges, there are many complex examples of
large ring formation by ring-closing metathesis. Note the dense
functionality in the following examples:
Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942.
Polar functional groups are thought to provide an internal
conformational bias for cyclization.
O
O
Ru
L
L
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Organic Reactions
2. Cross-Metathesis. Challenging due to the mixture of
products that are possible:
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Through the accumulation of data, alkenes can now be
characterized in terms of their reactivity toward crossmetathesis:
Type I
(fast homodimerization)
Type II
(slow homodimerization)
Type III
(no homodimerization)
Statistically:
Type IV
(spectator to CM)
terminal alkenes, allyl alcohols,
styrenes, allyl-silanes, allyl-sulfides,
protected allyl-amines
Acrylates, vinyl ketones, acrolein,
3°/2° allylic-alcohols, vinyl epoxides
1,1-disubstituted alkenes, phenyl vinylsulfone, 4° allylic carbons, protected
3° allylic-acohols
vinyl nitro-olefins, trisubstituted allylic
alcohols
J. Am. Chem. Soc., 2003, 125, 11360.
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Organic Reactions
This then allows for the design and execution of selective crossmetathesis reactions:
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More recently, Z-selective cross-metathesis catalysts have been
developed:
Hoveyda et al. Nature 2011, 471, 461
Putting it all together:
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