Organic Chemistry

Welcome to Chem 206
Fall Term, 2005, David A. Evans

This course is designed to introduce upper-level
undergraduates and beginning graduate
students to advanced topics in organic
chemistry. The course begins with a discussion
of bonding phenomena, an introduction to FMO
theory, and stereoelectronic effects. This
section will be followed by lectures in
conformational analysis in both cyclic and
acyclic systems. Following this introduction, a
discussion of the important classes of organic
reactions will be presented. Topics include
rearrangements, cycloadditions, carbonyl
additions, and enolate-based transformations.
Problems for this course may be accessed at the following website:

http://daecr1.chem.harvard.edu/problems/
Textbooks
Carey & Sundberg, Advanced Organic Chemistry, Parts A,B
Kirby, A. J. Stereoelectronic Effects (See DAE)
Fleming, I. Frontier Orbitals and Organic Chemical Reactions.
Web Problems (>500)
http://daecr1.chem.harvard.edu/problems/
D. A. Evans
An Introduction to Frontier Molecular Orbital Theory-1
http://www.courses.fas.harvard.edu/~chem206/
http://evans.harvard.edu/problems/
Chemistry 206
! Problems of the Day

The molecule illustrated below can react through either Path A or Path B to
form salt 1 or salt 2. In both instances the carbonyl oxygen functions as the
nucleophile in an intramolecular alkylation. What is the preferred reaction
path for the transformation in question?
O
Path A
Advanced Organic Chemistry
Chem 206
Br
N
H
N
O
H Br
Br
Path B
Lecture Number 1
Introduction to FMO Theory
Br
Br
N
O
H Br
This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in

Zuerich some years ago
! General Bonding Considerations

! The H2 Molecule Revisited (Again!)
! Donor & Acceptor Properties of Bonding & Antibonding States
! Hyperconjugation and "Negative" Hyperconjugation
! Anomeric and Related Effects
(First hr exam, 1999)

The three phosphites illustrated below exhibit a 750fold span in reactivity with
a test electrophile (eq 1) (Gorenstein, JACS 1984, 106, 7831).
! Reading Assignment for week:
(RO)3P
+
(RO)3PEl
El(+)
(1)
Kirby, Stereoelectronic Effects

OMe
Carey & Sundberg: Part A; Chapter 1
O P
O
Fleming, Chapter 1 & 2

Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf)
Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)
D. A. Evans
Monday,
September 19, 2005
O
O
O P OMe
O
O
B
Rank the phosphites from the least to the most nucleophilic and
provide a concise explanation for your predicted reactivity order.
An Introduction to Frontier Molecular Orbital Theory-1
D. A. Evans
Universal Effects Governing Chemical Reactions

There are three:
! Steric Effects
Nonbonding interactions (Van der Waals repulsion) between
substituents within a molecule or between reacting molecules
RO
! Stereoelectronic Effects
Geometrical constraints placed upon ground and transition states
by orbital overlap considerations.
Fukui Postulate for reactions:
"During the course of chemical reactions, the interaction of
Me
Nu:
Chem 206
Br
Me
SN2
Nu
Br:
R
R
major
! General Reaction Types

Radical Reactions (~10%):
Me
RO Me
Me2CuLi
molecular orbital (LUMO) in reacting species is very important

to the stabilization of the transition structure."
RO H
the highest filled (HOMO) and lowest unfilled (antibonding)
minor
Polar Reactions (~90%):
A + B
A(:) + B(+)
Lewis Base
! Electronic Effects (Inductive Effects):

The effect of bond and through-space polarization by
heteroatom substituents on reaction rates and selectivities
Inductive Effects: Through-bond polarization
Field Effects:
Through-space polarization
FMO concepts extend the donor-acceptor paradigm to

non-obvious families of reactions
! Examples to consider
+
2 Li(0)
2 LiH
CH3I +
Mg(0)
CH3MgBr
H2
Me
R
C
R
Br
SN1
+
R
Me + Br:
rate decreases as R becomes more electronegative
Lewis Acid
"Organic chemists are generally unaware of the impact of

electronic effects on the stereochemical outcome of reactions."
"The distinction between electronic and stereoelectronic effects is
not clear-cut."
Steric Versus Electronic Effects; A time to be careful!!
D. A. Evans
Chem 206
! Steric Versus electronic Effects: Some Case Studies

When steric and electronic (stereoelectronic) effects
lead to differing stereochemical consequences
Woerpel etal. JACS 1999, 121, 12208.
OAc
Me
TiCl4
EtO
SnBr4
Nu
R3Si
OAc
SnBr4
diastereoselection
93:7
H
OSiR3
OSiR3
H
AlCl3
stereoselection >95:5
O
OSiR3
stereoselection 99:1
SiMe3
diastereoselection
>94:6
OSiR3
Me
Me
OSiR3
O
R3SiO
Danishefsky et al JOC 1991, 56, 387
BnO
BnO
BnO
O
EtO2C
O
diastereoselection
8:1
(R)2CuLi
O
EtO2C
Ph N
Bu
OTBS
Bu3Al
R3
O Al O
EtO
H
H
Al
O TBS
R
only diastereomer
N
EtO2C
only diastereomer
OAc
Bu
OTBS
Yakura's
rationalization:
OAc
O
H
Ph N
Yakura et al
Tetrahedron 2000, 56, 7715
Ph
OAc
OAc
H
H
N
O
O
OTBS
AcO
AcO
60-94%
Ph
Mehta et al, Acc Chem. Res. 2000, 33, 278-286
Chem 206
The H2 Molecular Orbitals & Antibonds
D. A. Evans
Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients
The H2 Molecule (again!!)

Let's combine two hydrogen atoms to form the hydrogen molecule.
Mathematically, linear combinations of the 2 atomic 1s states create
two new orbitals, one is bonding, and one antibonding:
! Rule Two:
Each MO is constructed by taking a linear combination of the
individual atomic orbitals (AO):
Bonding MO
! Rule one: A linear combination of n atomic states will create n MOs.

!" (antibonding)
Antibonding MO
Energy
! Rule Three:
1s
1s
$1
H
$2
#E
"# = C*1!1 C*2!2
The coefficients, C1 and C2, represent the contribution of each AO.
#E
H
" = C1!1 + C2!2
(C1)2 + (C2)2 = 1
The squares of the C-values are a measure of the electron population

in neighborhood of atoms in question
! Rule Four: bonding(C1)2 + antibonding(C*1)2= 1
! (bonding)
Let's now add the two electrons to the new MO, one from each H atom:
In LCAO method, both wave functions must each contribute

one net orbital
Consider the pibond of a C=O function: In the ground state pi-CO
is polarized toward Oxygen. Note (Rule 4) that the antibonding MO
is polarized in the opposite direction.
#E1
H
1s
1s
$1
$# (antibonding)
H
$2
#E2
Energy
Energy
!" (antibonding)
! (bonding)
Note that #E1 is greater than #E2. Why?
$ (bonding)
D. A. Evans
Chem 206
Bonding Generalizations
! Bond strengths (Bond dissociation energies) are composed of a

covalent contribution (! Ecov) and an ionic contribution (! Eionic).
Bond Energy (BDE) = ! Ecovalent + ! Eionic
(Fleming, page 27)
! Orbital orientation strongly affects the strength of the resulting bond.

For " Bonds:
A
When one compares bond strengths between CC and CX, where X

is some other element such as O, N, F, Si, or S, keep in mind that
covalent and ionic contributions vary independently. Hence, the
mapping of trends is not a trivial exercise.
Better
than
For ! Bonds:
Useful generalizations on covalent bonding

! Overlap between orbitals of comparable energy is more effective
than overlap between orbitals of differing energy.
For example, consider elements in Group IV, Carbon and Silicon. We
know that C-C bonds are considerably stronger by Ca. 20 kcal mol-1
than C-Si bonds.
C
better than
Si
This is a simple notion with very important consequences. It surfaces

in the delocalized bonding which occurs in the competing anti
(favored) syn (disfavored) E2 elimination reactions. Review this
situation.
! Anti orientation of filled and unfilled orbitals leads to better overlap.

This is a corrollary to the preceding generalization.
There are two common situations.
C-SP3
! CSi
! CC
H3CSiH3 BDE ~ 70 kcal/mol

Bond length = 1.87
! CSi = 36 kcal/mol
! SiSi = 23 kcal/mol
! Weak bonds will have corresponding low-lying antibonds.

Formation of a weak bond will lead to a corresponding low-lying antibonding
orbital. Such structures are reactive as both nucleophiles & electrophiles
!* CX
LUMO
X
Better
than
lone pair
HOMO
!* CX
LUMO
lone pair
HOMO
Case-2: Two anti sigma bonds
This trend is even more dramatic with pi-bonds:

! CC = 65 kcal/mol
Si-SP3
H3CCH3 BDE = 88 kcal/mol

Bond length = 1.534
Case-1: Anti Nonbonding electron pair & CX bond
!" CSi
C-SP3
Si
!" CC
C-SP3
Better
than
X
A
Y
C
! CY
HOMO
!* CX
LUMO
Better
than
! CY
HOMO
!* CX
LUMO
D. A. Evans
Hyperconjugation, The Anomeric Effect, and More
Chem 206
Useful LIterature Reviews
Kirby, A. J. (1982). The Anomeric Effect and Related Stereoelectronic Effects at

Oxygen. New York, Springer Verlag.
Chemistry 206
Box, V. G. S. (1990). The role of lone pair interactions in the chemistry of the
monosaccharides. The anomeric effect. Heterocycles 31: 1157.
Box, V. G. S. (1998). The anomeric effect of monosaccharides and their

derivatives. Insights from the new QVBMM molecular mechanics force field.
Heterocycles 48(11): 2389-2417.
Graczyk, P. P. and M. Mikolajczyk (1994). Anomeric effect: origin and
consequences. Top. Stereochem. 21: 159-349.
Lecture Number 2
Stereoelectronic Effects-2
Juaristi, E. and G. Cuevas (1992). Recent studies on the anomeric effect.

Tetrahedron 48: 5019 (PDF)
Carey & Sundberg: Part A; Chapter 3 pp 151-156
! "Positive" and "Negative" Hyperconjugation

! Anomeric and Related Effects
Question: First hour Exam 2000 (Database Problem 34)
! Peracid & Dioxirane Epoxidation (Stereoelectronics)
Question 4. (15 points). The useful epoxidation reagent dimethyldioxirane (1) may be
prepared from "oxone" (KO3SOOH) and acetone (eq 1). In an extension of this epoxidation
concept, Shi has described a family of chiral fructose-derived ketones such as 2 that, in the
presence of "oxone", mediate the asymmetric epoxidation of di- and tri-substituted olefins
with excellent enantioselectivities (>90% ee) (JACS 1997, 119, 11224).
Kirby, Stereoelectronic Effects Chapters 1-5

Carey & Sundberg: Part A; Chapter 1, Chapter 3
Fleming, Chapter 1 & 2

Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf)
Me
R2

R1
D. A. Evans
Me
Me
Wednesday,
September 21, 2005
R2
KO3SOOH
CH3CN-H2O
pH 10.5
Me
Me
(1)
R2
O
(2)
R1
Me
O R2
1 equiv 2
oxone,
CH3CN-H2O
pH 10.5
Me
O
Me
>90% ee
Part A (8 points). Provide a mechanism for the epoxidation of ethylene with

dimethyldioxirane (1). Use three-dimensional representations, where relevant, to illustrate
the relative stereochemical aspects of the oxygen transfer step. Clearly identify the
frontier orbitals involved in the epoxidation.
D. A. Evans
Chem 206
Hyperconjugation: Carbocation Stabilization
! The interaction of a vicinal bonding orbital with a p-orbital is referred

to as hyperconjugation.
This is a traditional vehicle for using valence bond to denote charge
delocalization.
R
C
Physical Evidence for Hyperconjugation

Bonds participating in the hyperconjugative interaction, e.g. CR,
will be lengthened while the C(+)C bond will be shortened.
R
H
First X-ray Structure of an Aliphatic Carbocation
The graphic illustrates the fact that the C-R bonding electrons can
"delocalize" to stabilize the electron deficient carbocationic center.
1.431
[F5SbFSbF5]
Note that the general rules of drawing resonance structures still hold:
the positions of all atoms must not be changed.
+
C
100.6
Stereoelectronic Requirement for Hyperconjugation:
1.608
Me
Me
Me
Syn-planar orientation between interacting orbitals
The Molecular Orbital Description

T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349
!" CR
!" CR
+
C
The Adamantane Reference

(MM-2)
1.528
110
! CR
! CR
Me
Me
Me
! Take a linear combination of ! CR and CSP2 p-orbital:
"The new occupied bonding orbital is lower in energy. When you

stabilize the electrons is a system you stabilize the system itself."
1.530
D. A. Evans
Chem 206
"Negative" Hyperconjugation
! Delocalization of nonbonding electron pairs into vicinal antibonding

orbitals is also possible
R
H
H
""
H
H
""
H
H
This decloalization is referred to as "Negative" hyperconjugation
X+
antibonding !" CR
R:
H
""
filled
hybrid orbital
Anti Orientation
""
Since nonbonding electrons prefer hybrid orbitals rather that P

orbitals, this orbital can adopt either a syn or anti relationship
to the vicinal CR bond.
R:
""
antibonding !" CR
Syn Orientation
R
X+
H
H
filled
X hybrid orbital
""
! Overlap between two orbitals is better in the anti orientation as

stated in "Bonding Generalizations" handout.
The Molecular Orbital Description

!" CR
The Expected Structural Perturbations

X
Nonbonding
Spectroscopic Probe
! Shorter CX bond
X-ray crystallography
! Longer CR bond
X-ray crystallography
! Stronger CX bond
Infrared Spectroscopy
! Weaker CR bond
Infrared Spectroscopy
! Greater e-density at R
NMR Spectroscopy
! Less e-density at X
NMR Spectroscopy
pair
!!
! CR
Change in Structure
As the antibonding CR orbital

decreases in energy, the magnitude
of this interaction will increase
Note that ! CR is slightly destabilized
D. A. Evans
Lone Pair Delocalization: N2F2
The interaction of filled orbitals with adjacent antibonding orbitals can

have an ordering effect on the structure which will stabilize a particular
geometry. Here are several examples:
This molecule can exist as either cis or
trans isomers
Case 1: N2F2
F
F
N
The trans Isomer
filled
N-SP2
! The nonbonding lone pair orbitals in the cis isomer will be destabilizing
due to electron-electron repulsion.
! The individual CF dipoles are mutually repulsive (pointing in same
direction) in the cis isomer.
In fact the cis isomer is favored by 3 kcal/ mol at 25 C.
Let's look at the interaction with the lone pairs with the adjacent CF
antibonding orbitals.
The cis Isomer
F
filled
N-SP2
Now carry out the same analysis with the same 2

orbitals present in the trans isomer.
F
antibonding
!" NF
!" NF
(LUMO)
filled
N-SP2
(HOMO)
F
There are two logical reasons why the trans isomer should be more
stable than the cis isomer.
Chem 206
! In this geometry the "small lobe" of the filled N-SP2 is required to

overlap with the large lobe of the antibonding CF orbital. Hence, when
the new MO's are generated the new bonding orbital is not as stabilizing
as for the cis isomer.
Conclusions
! Lone pair delocalization appears to override electron-electron and
dipole-dipole repulsion in the stabilization of the cis isomer.
! This HOMO-LUMO delocalization is stronger in the cis isomer due
to better orbital overlap.
Important Take-home Lesson
Orbital orientation is important for optimal orbital overlap.
F
antibonding
!" NF
!" NF
(LUMO)
filled
N-SP2
(HOMO)
! Note that by taking a linear combination of the nonbonding and

antibonding orbitals you generate a more stable bonding situation.
! Note that two such interactions occur in the molecule even though
only one has been illustrated.
forms stronger pi-bond than
forms stronger
sigma-bond than
This is a simple notion with very important consequences. It surfaces in

the delocalized bonding which occurs in the competing anti (favored)
syn (disfavored) E2 elimination reactions. Review this situation.
D. A. Evans
The Anomeric Effect: Negative Hyperconjugation
! Since the antibonding CO orbital is a better acceptor orbital than the

antibonding CH bond, the axial OMe conformer is better stabilized by
this interaction which is worth ca. 1.2 kcal/mol.
The Anomeric Effect

It is not unexpected that the methoxyl substituent on a cyclohexane ring
prefers to adopt the equatorial conformation.
H
H
OMe
OMe
! Gc = +0.6 kcal/mol
What is unexpected is that the closely related 2-methoxytetrahydropyran
prefers the axial conformation:
H
O
Chem 206
preferred by 1.8 kcal/mol
Why is axial CCl bond longer ?
axial O lone pair!"# CCl
OMe
Other electronegative substituents such as Cl, SR etc also participate in

anomeric stabilization.
H
""
1.781
H
O
Cl H O O
Cl
1.819 Cl
This conformer
OMe
! Gp = 0.6 kcal/mol
"# CCl
""
That effect which provides the stabilization of the axial OR

conformer which overrides the inherent steric bias of the
substituent is referred to as the anomeric effect.
O
HOMO
Cl
" CCl
Let anomeric effect = A

$ Gp =
A =
$ Gc + A
The Exo-Anomeric Effect
$ Gp $ Gc
A = 0.6 kcal/mol 0.6 kcal/mol = 1.2 kcal/mol

Principal HOMO-LUMO interaction from each conformation is
illustrated below:
H
!!
OMe
!!
axial O lone pair!"# CH
H
OMe
axial O lone pair!"# CO
! There is also a rotational bias that is imposed on the exocyclic

COR bond where one of the oxygen lone pairs prevers to
be anti to the ring sigma CO bond
H
O
O
R O
O R
favored
A. J. Kirby, The Anomeric and Related Stereoelectronic Effects at Oxygen,

Springer-Verlag, 1983
E. Jurasti, G. Cuevas, The Anomeric Effect, CRC Press, 1995
D. A. Evans
The Anomeric Effect: Carbonyl Groups
Do the following valence bond resonance structures

have meaning?
Aldehyde CH Infrared Stretching Frequencies

Prediction: The IR CH stretching frequency for aldehydes is lower
than the closely related olefin CH stretching frequency.
For years this observation has gone unexplained.
Chem 206
!!
X
R
R
O
O
Me
!C=O
(cm-1)
CH3
1720
Me
Me
1750
! CH = 2730
cm -1
! CH = 3050 cm -1
Sigma conjugation of the lone pair anti to the H will weaken the bond.
This will result in a low frequency shift.
O
CBr3
Prediction: As X becomes more electronegative, the IR frequency

should increase
CF3
1780
Infrared evidence for lone pair delocalization into

vicinal antibonding orbitals.
The NH stretching frequency of cis-methyl diazene is 200 cm-1 lower
than the trans isomer.
Prediction: As the indicated pi-bonding increases, the XCO

bond angle should decrease. This distortion improves overlap.
Me
H
N
! NH = 2188 cm -1
R
C
Me
!* CX "O lone pair

Evidence for this distortion has been obtained by X-ray crystallography
Corey, Tetrahedron Lett. 1992, 33, 7103-7106
filled
N-SP2
Me
N
Me
N
H
! NH = 2317 cm -1
N
filled
N-SP2
..
H
antibonding
"# NH
antibonding
"# NH
H
! The low-frequency shift of the cis isomer is a result of NH bond

weakening due to the anti lone pair on the adjacent (vicinal)
nitrogen which is interacting with the NH antibonding orbital. Note
that the orbital overlap is not nearly as good from the trans isomer.
N. C. Craig & co-workers JACS 1979, 101, 2480.
The Anomeric Effect: Nitrogen-Based Systems
D. A. Evans
Observation: CH bonds anti-periplanar to nitrogen lone pairs are

spectroscopically distinct from their equatorial CH bond counterparts
CMe3
Me3C N
N
N
CMe3
Me3C
!" CH
H
H
H
Chem 206
Me3C N
N
N
Me3C
!G = 0.35kcal/mol
A. R. Katritzky et. al., J. Chemm. Soc. B 1970 135
N
HOMO
Favored Solution Structure (NMR)
! CH
Spectroscopic Evidence for Conjugation
Me
Infrared Bohlmann Bands

Characteristic bands in the IR between 2700
and 2800 cm-1 for C-H4, C-H6 , & C-H10 stretch
Bohlmann, Ber. 1958 91 2157
Reviews: McKean, Chem Soc. Rev. 1978 7 399
L. J. Bellamy, D. W. Mayo, J. Phys.
Chem. 1976 80 1271
NMR : Shielding of H antiperiplanar to N lone pair

H10 (axial): shifted furthest upfield
H6, H4: !" = " Haxial - " H equatorial = -0.93 ppm
Protonation on nitrogen reduces !" to -0.5ppm
H. P. Hamlow et. al., Tet. Lett. 1964 2553
J. B. Lambert et. al., JACS 1967 89 3761
MeN
NMe
MeN
NMe
Me N
N
N
N Me
Me
J. E. Anderson, J. D. Roberts, JACS 1967 96 4186
B Favored Solid State Structure (X-ray crystallography)

1.484
Bn
Me
N
N
Me
A
Bn
Me
1.453
1.453
Bn
N
Bn
N
1.459
Rationalize why B might be more stable than A.

A. R. Katrizky et. al., J. C. S. Perkin II 1980 1733
Me
1.457
D. A. Evans
Chem 206
Carboxylic Acids (& Esters): Anomeric Effects Again?

! Hyperconjugation:
! Conformations: There are 2 planar conformations.

O
(Z) Conformer
R'
(E) Conformer
O R'
Specific Case:
Methyl Formate
(Z) Conformer
Me
Me
!G = +4.8 kcal/mol
The (E) conformation of both acids and esters is less stable by 3-5 kcal/mol. If
this equilibrium were governed only by steric effects one would predict that the
(E) conformation of formic acid would be more stable (H smaller than =O).
Since this is not the case, there are electronic effects which must also be
considered. These effects will be introduced shortly.
Let us now focus on the oxygen lone pair in the hybrid

orbital lying in the sigma framework of the C=O plane.
!* CO
In the (Z) conformation this

lone pair is aligned to overlap
with !* CO.
O
R
R
(E) Conformer
R
R
In the (E) conformation this

lone pair is aligned to overlap
with !* CR.
!* CR
O
! Rotational Barriers: There is hindered rotation about the =COR bond.

R
These resonance structures suggest

hindered rotation about =COR bond.
This is indeed observed:
O
barrier ~ 10-12
kcal/mol
Since !* CO is a better acceptor than !* CR

(where R is a carbon substituent) it follows that
the (Z) conformation is stabilized by this interaction.
O
R
O
O
R'
Rotational barriers are ~ 10-12

kcal/mol. This is a measure of the
strength of the pi bond.
R
O
R
R
O
R
!G ~ 2-3
kcal/mol
! Lone Pair Conjugation: The oxygen lone pairs conjugate with the C=O.
Esters versus Lactones: Questions to Ponder.

Esters strongly prefer to adopt the (Z) conformation while
small-ring lactones such as 2 are constrained to exist in the
(Z) conformation. From the preceding discussion explain the
following:
O
1
Et
CH3CH2
O
O
O
2
1) Lactone 2 is significantly more susceptible to nucleophilic

attack at the carbonyl carbon than 1? Explain.
R'
Energy
O C
The filled oxygen p-orbital interacts with pi (and pi*)

C=O to form a 3-centered 4-electron bonding system.
R
SP2 Hybridization
! Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridization

is driven by system to optimize pi-bonding.
versus
2) Lactone 2 is significantly more prone to enolization than 1?

In fact the pKa of 2 is ~25 while ester 1 is ~30 (DMSO). Explain.
3) In 1985 Burgi, on carefully studying
O
O
O
"
" !
!
" !
the X-ray structures of a number of
lactones, noted that the O-C-C (!) &
O
O
O
O-C-O (") bond angles were not equal.
Explain the indicated trend in bond
angle changes.
!#" = 12.3 !#" = 6.9 !#" = 4.5
Anomeric Effects in DNA Phosphodiesters
D. A. Evans
Calculated Structure of ACGTGC Duplex
Chem 206
The Phospho-Diesters Excised from Crystal Structure
Guanine
1B
Cytosine
Cytosine
2B
1A
Phosphate-1A
Phosphate-1B
Thymine
Adenine
The Anomeric Effect

Acceptor orbital hierarchy: !* POR * > !* PO
R
! O
O
O
! O
! O
O
O
R
Gauche-Gauche conformation
! O
R
P
! O
O
O
R
R
P
! O
O
O
R
! O
Anti-Anti conformation
Gauche-Gauche conformation affords a better donor-acceptor relationship
Phosphate-2A
Phosphate-2B
Oxygen lone pairs may establish a simultaneous hyperconjugative

relationship with both acceptor orbitals only in the illustrated
conformation.
Plavec, et al. (1996). How do the Energetics of the Stereoelectronic Gauche &
Anomeric Effects Modulate the Conformation of Nucleos(t)ides?
Pure Appl. Chem. 68: 2137-44.
D. A. Evans
! The General Reaction:
R
The transition state:

R
+
R
Chem 206
Olefin Epoxidation via Peracids: An Introduction
HOMO
!CC
"
OH
"
LUMO
"*OO
OH
note labeled oxygen is transferfed
O-O bond energy: ~35 kcal/mol

R
HOMOLUMO Interactions for Peracid Epoxidation

Since 2 CO bonds are formed in the epoxidation reaction, there are two
HOMOLUMO pairs that should be considered. They are illustrated below.
View from below olefin
! Reaction rates are governed by olefin nucleophilicity. The rates of

epoxidation of the indicated olefin relative to cyclohexene are provided
below:
OH
OH
LUMO "*OO
HOMO O lone pair
1.0
OAc
0.6
0.05
0.4
! The indicated olefin in each of the diolefinic substrates may be

oxidized selectively.
Me
Me
Me
Me
Me
Me
HOMO !CC
LUMO !#CC
Me
H
Me
Me
D. A. Evans
R
+
R
Chem 206
Olefin Epoxidation with Dioxiranes
HOMO1
!CC
LUMO2
!"CC
!
O
!
R
LUMO1
#*OO
HOMO2
O lone pr
Asymmetric Epoxidation with Chiral Ketones
Review: Frohn & Shi, Syn Lett 2000, 1979-2000 (PDF)

R
Me
chiral catalyst
O
O
O
O
Me
R2
Me
O R2
Me
Transition State for the Dioxirane Mediated Olefin Epoxidation

R1
planar
spiro
>95% ee
! Synthesis of the Dioxirane Oxidant
O
S
Me
oxone
Me
O
F3C
Me
oxone
CF3
O
F3C
O
Me
O
CF3
Me
Ph
Ph
Ph
84% ee
92% ee
Me
Me
R
O
"
Synthetically Useful Dioxirane Synthesis

O
R2
Question 4. (15 points). The useful epoxidation reagent dimethyldioxirane (1) may be
prepared from "oxone" (KO3SOOH) and acetone (eq 1). In an extension of this epoxidation
concept, Shi has described a family of chiral fructose-derived ketones such as 2 that, in the
presence of "oxone", mediate the asymmetric epoxidation of di- and tri-substituted olefins
with excellent enantioselectivities (>90% ee) (JACS 1997, 119, 11224).
O
Me
SO3
(Oxone)
R1
Question: First hour Exam 2000 (Database Problem 34)
Houk, JACS, 1997, 12982.
Ph
Ph
stabilizing Olp ! "* C=C

cis olefins react ~10 times faster than trans
oxone, CH3CN-H2O
pH 7-8
Me
rotate 90
K+ O
R2
co-distill to give
~0.1 M soln of
dioxirane in acetone
co-distill to give
~0.6 M soln of dioxirane
in hexafluoroacetone
R2
R1
R2
KO3SOOH
Me
CH3CN-H2O
pH 10.5
Me
(1)
R2
O
(2)
R1
Me
O R2
1 equiv 2
oxone,
CH3CN-H2O
pH 10.5
Me
O
Me
>90% ee
Part A (8 points). Provide a mechanism for the epoxidation of ethylene with

dimethyldioxirane (1). Use three-dimensional representations, where relevant, to illustrate
the relative stereochemical aspects of the oxygen transfer step. Clearly identify the
frontier orbitals involved in the epoxidation.
Part B (7 points). Now superimpose chiral ketone 2 on to your mechanism proposed
above and rationalize the sense of asymmetric induction of the epoxidation of trisubstituted
olefins (eq 2). Use three-dimensional representations, where relevant, to illustrate the
absolute stereochemical aspects of the oxygen transfer step.
Donor-Acceptor Properties of Bonding and Antibonding States
D. A. Evans
Donor Acceptor Properties of C-C & C-O Bonds

Consider the energy level diagrams for both bonding & antibonding
orbitals for CC and CO bonds.
Chem 206
Hierarchy of Donor & Acceptor States

Following trends are made on the basis of comparing the bonding and
antibonding states for the molecule CH3X where X = C, N, O, F, & H.
!* C-C
!-bonding States: (CX)
!* C-O
CH3CH3
C-SP3
C-SP3
CH3H
CH3NH2
very close!!
O-SP3
CH3OH
CH3F
decreasing !-donor capacity

! C-C
poorest donor
! C-O
! The greater electronegativity of oxygen lowers both the bonding

& antibonding C-O states. Hence:
! ! CC is a better donor orbital than ! CO
!-anti-bonding States: (CX)

CH3H
! !"CO is a better acceptor orbital than !"CC
For the latest views, please read

CH3CH3
CH3NH2
Donor Acceptor Properties of CSP3-CSP3 & CSP3-CSP2 Bonds
CH3OH
!* CC
!* CC better acceptor
C-SP3
C-SP3
C-SP2
CH3F
Increasing !"-acceptor capacity
best acceptor
The following are trends for the energy levels of nonbonding states
of several common molecules. Trend was established by
photoelectron spectroscopy.
Nonbonding States
! CC
better donor
! CC
! The greater electronegativity of CSP2 lowers both the bonding &

antibonding CC states. Hence:
! ! CSP3-CSP3 is a better donor orbital than ! CSP3-CSP2
! !"CSP3-CSP2 is a better acceptor orbital than !"CSP3-CSP3
H3P:
H2S:
H3N:
H2O:
HCl:
decreasing donor capacity
poorest donor
D. A. Evans
Electrons in 2S states "see" a greater effective nuclear charge

than electrons in 2P states.
There is a linear relationship between %S character &

Pauling electronegativity
This becomes apparent when the radial probability functions for S

and P-states are examined: The radial probability functions for the
hydrogen atom S & P states are shown below.
NSP
4.5
2 S Orbital
2 S Orbital
Pauling Electronegativity
1 S Orbital
Radial Probability
100 %
100 %
Radial Probability
Chem 206
Hybridization vs Electronegativity
NSP2
NSP3
3.5
SP
CSP2
2.5
CSP3
2 P Orbital
2
20
3 S Orbital
25
30
35
40
45
50
55
% S-Character
There is a direct relationship between %S character &

hydrocarbon acidity
3 P Orbital
60
CH4 (56)
55
S-states have greater radial penetration due to the nodal properties of the wave
function. Electrons in S-states "see" a higher nuclear charge.
Least stable
CSP3
Most stable
CSP2
Pka of Carbon Acid
Above observation correctly implies that the stability of nonbonding electron

pairs is directly proportional to the % of S-character in the doubly occupied orbital
50
45
C6H6 (44)
40
35
CSP
PhCC-H (29)
30
The above trend indicates that the greater the % of S-character

at a given atom, the greater the electronegativity of that atom.
25
20
25
30
35
40
% S-Character
45
50
55
D. A. Evans
Stereoelectronic Effects Part 3
Chem 206

Speculate on the mechanism of the following transformation

O
O
S
Chemistry 206
CH3
SO3
Nu:
Nu
CH3

Lecture Number 3
Stereoelectronic Effects-3
! Baeyer-Villiger Reaction: Stereoelectronic Effects
The molecule illustrated below can react through either Path A or Path B to
form salt 1 or salt 2. In both instances the carbonyl oxygen functions as the
nucleophile in an intramolecular alkylation. What is the preferred reaction
path for the transformation in question?
O
Path A
O
Br
N
H
Br
N
O
H Br
Br
Path B
! The SN2 Reaction: Stereoelectronic Effects
Br
N
O
H Br
! Baldwin's Rules for Ring Closure
This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in

Zuerich some years ago
Read Kirby, Chapter 5, Cary & Sundberg, Chapter 5

Johnson, C. D. (1993). Stereoelectronic effects in the formation of 5and 6-membered rings: the role of Baldwin's rules.
Acc. Chem. Res. 26: 476-82. (Pdf)
Beak, P. (1992). Determinations of transition-state geometries by the
endocyclic restriction test: mechanisms of substitution at
nonstereogenic atoms. Acc. Chem. Res. 25: 215. (Pdf)
D. A. Evans
Friday,
September 23, 2004

Propose mechanisms for the following reactions
HO
R
O
H+
HO
R
O
OMe
HN NH
NH2NH2
Me
Me
D. A. Evans
CMe3
Let RL and RS be Sterically large and small substituents.

O
RL
O
+ RCO3H
RS
RL
RCO2H
Me
O
RS
RL
major
RS
Me
+ RCO3H
kR
O
R
minor
Me
CH3CH2
72
CH3(CH2)2
150
(CH3)3C
830
PhCH2
>2000
major
Me
+ CF3CO3H
O
kMe
C
R
kR / KMe
Me
O
- MeCO2H
H
O
Favored
H
Migrating group
CMe3
C
O
Me3C
O
CMe3
The major product is that wherein oxygen has been inserted into
the RLC=O bond.
Chem 206
The Baeyer-Villiger Reaction: Stereoelectronic Effects
O
Me
OH
O
Me
CMe3
O
R
Conformer A
Me
O
minor
RS
The Intermediate
OH
C
RL
Disfavored
Migrating group
Me
Me3C
OH
O
2. The COOC' dihedral angle will be ca. 60 due to the gauche

effect (O-lone pairsCO).
This gauche geometry is probably reinforced by intramolecular
hydrogen bonding as illustrated on the opposite page:
CMe3
O
R
The important stereoelectronic components to this rearrangement:

1. The RLCOO dihedral angle must be180 due to the HOMO
LUMO interaction -RLC with OO.
Me
Conformer B
The destabilizing
gauche interaction
Steric effects destabilize Conformer B relative to Conformer A;

hence, the reaction is thought to proceed via a transition
state similar to A.
For relevant papers see:
Crudden, Angew. Chem. Int. Ed 2000, 39, 2852-2855 (pdf)
Kishi, JACS 1998, 120, 9392 (pdf)
D. A. Evans
Chem 206
Three-Center Bonds: A Review

Case 3: 2 p-Orbitals; 1 s-orbital
Consider the linear combination of three atomic orbitals. The resulting

molecular orbitals (MOs) usually consist of one bonding, one nonbonding
and one antibonding MO.
Case 1: 3 p-Orbitals
pi-orientation
antibonding
2
antibonding
nonbonding
Energy
bonding
nonbonding
Case 4: 2 s-Orbitals; 1 p-orbital
Do this as an exercise
bonding
Note that the more nodes there are in the wave function, the higher its energy.
H2C
CH
+
CH2 Allyl carbonium ion: both pi-electrons in bonding state
Examples of three-center bonds in organic chemistry

A. H-bonds: (3center, 4electron)
O
Allyl Radical: 2 electrons in bonding obital plus one in

nonbonding MO.
H2C
CH
CH2
H2C
CH
Allyl Carbanion: 2 electrons in bonding obital plus 2 in

CH2 nonbonding MO.
The acetic acid dimer is

stabilized by ca 15 kcal/mol
B. H-B-H bonds: (3-center, 2 electron)

H
B
Case 2: 3 p-Orbitals
Energy
O
CH3
sigma-orientation
CH3
H
B
H
H
B
diborane stabilized by 35 kcal/mol

antibonding
C. The SN2 Transition state: (3center, 4electron)
3
nonbonding
Nu
C
H
bonding
The SN2 transition state approximates a case 2

situation with a central carbon p-orbital
H
Br
H
The three orbitals in reactant molecules used are:

1 nonbonding MO from Nucleophile (2 electrons)
1 bonding MO ! CBr (2 electrons)
1 antibonding MO !* CBr
D. A. Evans
Why do SN2 Rxns proceed with backside displacement?
!
Nu
!
X
C
H
Nu C
H X:
Given the fact that the LUMO on the electrophile is the CX antibonding
orblital, Nucleophilic attack could occur with either inversion or retention.
HOMO
El(+)
H
H
LUMO
Nu C
M+
Rb
H
Rb
Ra
C
H
Rb
M
C
!+
Ra
H
Rb
El !+
El
M+
Ra
Ra
El(+)
LUMO
C
H
Rb
!!
!!
H
Rb
HOMO
Inversion
El(+)
Retention
Examples
bonding
antibonding
Br2
!!
HOMO
Li
Nu
Fleming, page 75-76
Rb
Expanded view of !*CX
LUMO
Ra
!+
M
!!
Nu
Overlap from this geometry results
in no net bonding interaction
Constructive overlap between

Nu & !*CX
H
Rb
!+
Nu
Ra
Retention
El(+)
H
H
Ra
Ra
R
!!
Inversion
Retention
Inversion
Nu
Electrophilic substitution at saturated carbon may occur

with either inversion of retention
R
Nu:
Chem 206
Substitution Reactions: General Considerations
Br
predominant inversion
CO2
CO2Li
H
predominant retention
Stereochemistry frequently determined by electrophile structure

See A. Basu, Angew. Chem. Int. Ed. 2002, 41, 717-738 (PDF)
SN2 Reaction: Stereoelectronic Effects
D. A. Evans
Related Cases: " The Endocyclic Restriction Test"
Nu:
Nu
Chem 206
Nu
X:
SO3CH3
(CH3)2N
SO3
(CH3)3N
X
What is the absolute requirement for the NuCX bond angle??
180 +/ ??
Me
Me
Nu:
!
C
Nu
exclusively
intermolecular
O
H
King, et al. 1982 Chem Commun. 175

King, et al. 1982 Tetrahedron Lett. 23, 4465
"tethered reactants"
Eschenmoser: Tether Nu and X
"constrained transition state"
SO3
SO3CH3
N(CH3)3
N(CH3)2
Eschenmoser, Helv. Chim Acta 1970, 53, 2059 (PDF)

O
O
S
CH3
SO3
Nu:
Nu
CH3
Nu:
16% intramolecular
84% intermolecular
C
O
S
O
10-membered transition structure
O
H
Me
O
S
Me
C H
H
Intramolecular option
is not tenable
The reaction illustrated above proceeds exclusively through bimolecular

pathway in contrast to the apparent availability of the intramolecular path.
Hence, the NuCX 180 transition state bond angle must be rigidly
maintained for the reaction to take place.
"Determinations of transition-state geometries by the endocyclic restriction test:

mechanisms of substitution at nonstereogenic atoms",
Peter Beak,
Acc. Chem. Res.; 1992 25, 215-222 (PDF)
D. A. Evans
Rules for Ring Closure: Introduction
"Rules for Ring Closure: Baldwin's Rules"
Chem 206

Propose mechanisms for the following reactions
Kirby, "Stereoelectronic Effects" Chapters 4, 5
HO

Johnson, C. D. (1993). Stereoelectronic effects in the formation of 5and 6-membered rings: the role of Baldwin's rules.
Acc. Chem. Res. 26: 476-82. (Handout)
H+
HO
R
O

endocyclic restriction test: mechanisms of substitution at
nonstereogenic atoms. Acc. Chem. Res. 25: 215. (Handout)
OMe
HN NH
NH2NH2
Me
Me
Problem 689. Predict the product of the reaction below. Include a

rationalization based on a detailed analysis of competing transition
state geometries.
MeO
Cl
DBU, THF
OEt
64%
Problem 724. Equation (1) is a typical example of an Arbuzov

Rearrangement while Equationo (2) is an Arbuzov variant carried out with an
aldehyde.
BnBr
(1)
P(OMe)3
Sir Jack Baldwin

The Primary Literature
Baldwin, J. Chem. Soc., Chem. Comm. 1976, 734, 736.
Baldwin, J. Chem. Soc., Chem. Comm. 1977 233.
Baldwin, J. Org. Chem. 1977, 42, 3846.
Baldwin, Tetrahedron 1982, 38, 2939.
O
(2)
+
Ph
P(OMe)3
O
+
Ph
P
OMe
MeO
Me
O
Ph
P
OMe
MeO
Please comment on the mechanism of this transformation
MeBr
Jack Baldwin, Bristol Symposium, April, 2004
D. A. Evans, J. Johnson
Rules for Ring Closure: Introduction
Ring Closure and Stereoelectronic Considerations

An Examination of Baldwin's Rules
"Baldwin's Rules" provides a qualitative set of generalizations on the
probability of a given ring closure.
Chem 206
C. Nucleophilic ring closures sub-classified according to hybridization

state of electrophilic component:
(tetrahedral = tet; trigonal = trig; digonal = dig)
D. Nucleophilic ring closures further subclassified according to size of
the fomed ring. For example:
There are circumstances where the "rules" don't apply.

! They do not apply to non-first-row elements participating in the
cyclization event. The longer bond lengths and larger atomic radii of
2nd row elements result in relaxed geometrical constraints.
5-exo-tet
X
Y
For example, a change in a heteroatom from O to S could result in

relaxation of a given geometric constraint.
Y
5-exo-trig
endo
X = O vs S
Y
Y
5-exo-dig
X
Y
! The "rules" do not apply to electrocyclic processes.
Required trajectories (Baldwin):

Nomenclature
Classes of Ring Closing Processes
! = 180 "
!
Y
A. Exo-cyclization modes identified by the breaking bond

being positioned exocyclic to the forming cycle.
exo
Y
Y
B. Endo-cyclization modes identified by the breaking bond
being positioned endocyclic to the forming cycle.
X
"
* ! # 120 *
endo
X = first-row element
N, O
! = 109 "
!
Y
!
Y
Will come
back to this
case later
!
Y
Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
Rules for Ring Closure: SP3 Carbon & Related Systems
FRST-PLATTNER RULE
Tetrahedral Carbon
All exo cyclization modes are allowed: (n-exo-tet, n = 3!)
exo
Chem 206
There are stereoelectronic issues to consider for n-exo-tet cyclizations
In this simple model, the transition-state leading to 1 involves the

diaxial orientation of nucleophile and leaving group. This orientation
affords the best overlap of the anti-bonding CY orbital and the
nonbonding electron pairs on the nucleophile O.
In the formation of the diastereomeric epoxide 2, the proper
alignment of orbitals may only be achieved by cyclization through the
less-favored boat conformer. Accordingly, while both cyclizations are
"allowed", there are large rate differences the the rates of ring closure.
Formation of 3-Membered Rings (3-exo-tet)

H H
X
C
H2
C
H2
CH2
+ Y
C
H2
While the FRST-PLATTNER RULE deals wilth the microscopic

reverse, in the opening of epoxides by nucleophiles, the
stereoelectronic arguments are the same.
Stereoelectronic Effects in Epoxide Ring Cleavage

Nu
Conformational Effects in Epoxide Ring Formation/cleavage

Those stereoelectronic effects that operate in ring cleavage also
influence ring formation. Consider a rigid cyclohexene oxide system:
Y
H
O
H
H
chair
boat
O !
HO
Me3C
H
H
Me
Nu-
Nu
Nu
Me
O
H
Nu-
H
O
HO
Y
O
Me3C
slower
1 O
O
Y !
Me3C
faster
H
Nu-
Me3C
HO
Tetrahedral Carbon
Case 2: King, J.C.S. Chem. Comm., 1979, 1140.
Endo cyclization modes that are disallowed

(n-endo-tet, n = 3!"9)
8-endo-tet
disfavored
S
O
Me
NMe2
endo
Y
C(SP3)
SO2OMe
NMe2
The stereoelectronic requirement for a 180 XCY bond angle is only

met when the endo cyclization ring size reaches 9 or 10 members.
Case 1: Eschenmoser, Helvetica Chim. Acta 1970, 53, 2059.
O
O
S
CX3
O
NaH
6-endo-tet
disfavored
O
S
O
CX2I
NaH
6-exo-tet
favored
OCX2
Rxn exclusively
intramolecular
CY3
NMe3+
8-endo-tet
disfavored
SO3
NMe3+
Rxn exclusively
intermolecular
SO3
9-endo-tet
borderline
NMe3+
Conclusions
Allowed endo cyclization modes will require transition state ring sizes
of at least nine members.
CY3
Cyclization exclusively intermolecular. However the exocyclic analog

is exclusively intramolecular
O
Intramolecular epoxidation has also been evaluated
CY3
84% intermolecular,
16% intramolecular
OCX3
Rxn exclusively
intermolecular
(lecture 2)
NMe2
O
S
SO2OMe
Rxn exclusively
intermolecular
Chem 206
CY3
Beak, JACS 1991, 113, 6281.
O
Cl
OOH
8-endo-tet
disfavored
Cl
CO2H
n = 1: rxn exclusively intermolecular

n = 9: rxn is intramolecular
Beak states that the conclusions made with carbon

substitution also hold for oxygen atom transfer.
endocyclic restriction test: mechanisms of substitution at nonstereogenic
atoms. Acc. Chem. Res. 25: 215.
D. A. Evans
Olefin Epoxidation via Peracids: An Intramolecular Case
The General Reaction:

R
HOMO
CC
Per-arachidonic acid Epoxidation

R
+
R
Chem 206
OH
LUMO
*OO
Me
OH
The transition state:
View from below olefin
Per-arachidonic acid Epoxidation
Me
Me
!
O
Which olefin is selectively epoxidized??
E. J. Corey, JACS 101, 1586 (1979)

For a more detailed study see P. Beak, JACS 113, 6281 (1991)
For theoretical studies of TS see R. D. Bach, JACS 1991, 113, 2338
R. D. Bach, J. Org. Chem 2000, 65, 6715
Rules for Ring Closure: SP3 Carbon Versus Silicon
Tetrahedral Silicon
Chem 206
Brook Rearrangements
Explain what drives this rearrangement.
All Endo-Tet cyclization modes are allowed
Me
Si CMe3
TBS =
Me
TBSO
Y
Si(SP3)
Si
OMe Me
OH
KHMDS
Bu3Sn
endo
OH
THF, -78 C
94%
TMS
O
OR
Ph
RO OR
Me
fails!
Ph
OMe
Me
O
RO P
OTMS
O (1)
P
R
RO OR
SiR3
O
RO P
Si
OMe
Calter, M. A. Ph. D. Thesis, Harvard University, 1993.
Silicon may readily proceed through a hypervalent intermediate.
OTBS
Bu3Sn
R
OR
O (2)
RO OR
RO OR
Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation

Strategies," Tetrahedron 2001, 57, 2065-2084
Inorg. Chem. 1984, 23, 1378

O
R
3S +P
3D
SiR3
Li
R3Si
El(+)
Li
[1,2] Si
R
R3Si
R3Si
R
Li
R
El(+)
El
R
Trigonal Carbon
Endo cyclization modes that are disallowed
(3 to 5-endo-trig)
CO2Me
NH2
n-endo-trig
X
MeO2C
X
C
X = first-row element
The 5-endo-trig cyclization is a watershed case
Case 1: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
distance from reacting centers: 2.77

CO2Me
base
CO2Me
OH
5-endo-trig
Disfavored
however
CO2Me
CO2Me
base
S
SH
Second row atom relaxes the cyclization geometrical requirement

Case 2: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736.
MeO2C
MeO2C
CO2Me
X
NH2
CO2Me
HN
5-endo-trig
0%
MeO2C
HN
O
5-exo-trig
100%
It is possible that a "nonvertical"

trajectory is operational like that
suspected in C=O addition
Chem 206
Case 2: continued...
MeO2C
Apparent exceptions to disallowed 5-endo-trig cyclization process

MeO2C
CO2Me
X
NH2
CO2Me
HN
N
5-endo-trig
0%
5-exo-trig
100%
HN
O
CO2Me
R1HC
Control experiment: Intermolecular reaction favors conjugate addtion.

PhCH2NH2
CO2Me
CO2Me
H
N
O
100%
Ph
Ph
OK
NH2NH2
OMe
Ph
1) EtO2CCl, pyridine
2) NH2NH2
NH
Ph
R2
R1
HN
200 oC
(CH2OH)2 R
HO
R
O
OH
( )2
65 oC
Ph
CO2Me
NH2NH2
HN
NH2
5-exo-trig
O
HN
H2O
H+
H2O
R
O
OH 5-exo-tet
( )2
favored ?
OH
R
O
( )2
5-endo-trig
disfavored ?
5-endo-trig
R
Ph
H+
O
OMe
(CH2OH)2
O
H+
MeI
CO2Me
R2
HN
3:1
Grigg, J. Chem. Soc., Chem. Commun. 1980, 648.
NH
R2
CO2Me
R1 = aryl, R2 = aryl, alkyl
H2N
Ph
CO2Me
R1
Does the illustrated

ketalization process
necessarily violate "the
rules"?
O
HN
65 oC
0%
Case 3:
OH
CO2Me
KOtBu
CO2Me
Me
Me
H
N
Ph
Ph
+
N
CH3CO2H
Filer, J. Am. Chem. Soc. 1979, 44, 285.
MeO2C
Me
Chem 206
NH
Johnson, C. D. (1993). Stereoelectronic effects in the formation of 5- and 6membered rings: the role of Baldwin's rules.
Acc. Chem. Res. 26: 476-82.
D. A. Evans
Acyclic Conformational Analysis-1
Chem 206
Problem 61. The following stereoselective hydroboration has been reported by Kishi in
his synthesis of monensin (JACS 1979, 101, 259). Provide the stereostructure of the
major product and rationalize the stereochemical outcome as indicated in the directions.
Chemistry 206
BH3, THF
OCH2Ph

Lecture Number 4
Baldwin's Rules-2
Conformational Analysis-1
Me
H2O2, -OH
Me
Problem 68. The following stereoselective enolate alkylation has been reported by Kim
(Tetrahedron Lett. 1986, 27, 943). Provide the stereostructure of the major product and
rationalize the stereochemical outcome as indicated in the directions.
Me
LiNR2
TsO
! Baldwin's Rules for Ring Closure
CO2Me
Ethane, Propane, Butane & Pentane Conformations
Simple Alkene Conformations
! Reading Assignment for week

A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070
Conformation Design of Open-Chain Compounds (handout)
The product ?
Stereoselection: 8/1
The product ?
Stereoselection: >40:1
C4H9
Problem 722. Carbonium ion A has been calculated to be 38

kcal/mol more stable than carbonium ion B (Jorgensen JACS 1985,
107, 1496). The profound stabilization of carbonium ions by silicon in
this fashion is referred to as the "beta-silicon effect". For example,
the SN1 solvolysis reaction of 1 is 10+12 times as fast as the
corresponding reaction of 2. The solvolysis of 2 leads to the olefin.
For a good review see: Lambert Acc. Chem. Res. 1999, 32, 183-190
R3Si
CH2
A
vs
R3 C
CH2
B
The Ethane Barrier Problem

F. Weinhold, Nature 2001, 411, 539-541
"A New Twist on Molecular Shape" (handout)
F. M. Bickemhaupt & E. J. Baerends, Angew. Chem. Int. Ed. 2003, 42, 41834188,"The Case for Steric Repulsion Causing the Staggered Conformation
in Ethane" (handout)
F. Weinhold,, Angew. Chem. Int. Ed. 2003, 42, 4188-4194,"Rebuttal of the
BikelhauptBaerends Case for Steric Repulsion Causing the staggered
Connformation of Ethane" (handout)
D. A. Evans
Monday,
September 26, 2005
SiMe3
Me3C
H
H
1
OCOCF3
Part A: Identify the HOMO

LUMO interactions in the SN1
reactions of 1 and 2.
Me
Solvolysis (CF3CH2OH)
k1
k2
= 2.4 x 10+12
Me3C
H
H
CH2
1-LUMO
2-LUMO
1-HOMO
2-HOMO
OCOCF3
CH2
Chem 206
Trigonal Carbon: Exocyclic Enolate Alkylation

exo
O
C
C
Y-
! By definition, an exo-tet cyclization, but stereoelectronically

behaves as an endo trig.
Me
Me
Me
Me
Br
Me
(1)
Me
MO
only observed
product
However:
Me
Me
KOt-Bu or LDA
Me
O
Me
Br
Me
> 95% by NMR
Baldwin, J. Chem. Soc., Chem. Commun. 1977, 233.
! Given the failure of the enolate alkylation shown above (eq 1),
explain why these two cyclizations are successful.
Br
base
NHAr
Ar
R
NH
R
O
Favorskii Rearrangement (Carey, Pt B, pp 609-610)

Your thoughts on the mechanism
Ar
OMs
base
O
N
Ar
Cl MeO
HCl
CO2Me
MeO
Rules for Ring Closure: SP2 & SP Carbon & Related Systems
Trigonal Carbon: Intramolecular Aldol Condensations
Digonal Carbon: Cyclizations on to Acetylenes
Baldwin, Tetrahedron 1982, 38, 2939
MO
R
(Enolendo)-Exo-trig
DIGONAL: Angle of approach for attack on triple bonds
Baldwin:
Nu-
120
YM
Favored: 6-7-(enolendo)-exo-trig
Disfavored: 3-5-(enolendo)-exo-trig
- 3 and 4-Exo-dig are disfavored

- 5 to 7-Exo-dig are favored
- 3 to 7-Endo-dig are favored
120
E+
(Enolexo)-exo-trig
X
O
MO
R
Ab initio SCF 4-31G calculations for the interaction of

hydride with acetylene:
YM
R
H
Favored: 3-7-(enolexo)-exo-trig
5-(Enolendo)-Exo-trig
Me
H
H
Me
H
Me
Me
O
Me
H
Me
STO-3G minimal basis set
110o -120o
1.5-2.0
favored
Me
Me
Houk, J.ACS.1979, 101, 1340.
O
I
4-31G basis set
148o H
C
C
H 156o 1.22
6-(Enolendo)-Exo-trig
Me
127 o
2.13
H
O
Chem 206
Dunitz, Helv Chim. Acta

1978, 61, 2538.
O
III
Crystal Structures do not support Baldwin
O
II
Statistical Distribution, (I + II)/III = 2:1

Experimental Distribution,
= 0:100
(KOH, MeOH, r.t., 5 min, 77% y.)
C aution: Baldwin's conclusions assume that the RDS is ring

closure; however, it is well known (b y some!) that the rate
determining step is dehydration in a b ase-catalyzed aldol
condensation.
N
O-
2.92
N+
104o
2.44
93o
86o
J. Dunitz and J. Wallis J. C. S. Chem. Comm. 1984, 671.
Rules for Ring Closure: SP Carbon & Related Systems
Endo Digonal versus Endo Trigonal Cyclizations
Chem 206
! Indole synthesis:
CH3
5-endo-trig
N
2 equiv. LDA
CH2R
2 equiv. RX
-78 oC
R = Me, Bu, CO2Me

LiTMP
X:
In-plane approach;
nucleophile lone pair is
orthogonal to !*
Out-of-plane approach;
nucleophile lone pair can't
achieve Brgi-Dunitz angle
R
Saegusa, J. Am. Chem. Soc. 1977, 99, 3532.
5-endo-dig
Li+
! Spiro dihydrofuranones:
:X
Allowed due to in-plane pi orbitals
Li
HO
OMe
MeO
KOtBu
OMe
X
For an opposing viewpoint to Baldwin's view of nucleophile trajectories, see
Menger's article on directionality in solution organic chemistry:
Tetrahedron 1983, 39, 1013.
Me
NaOMe
MeOH
Me
Ph
Magnus, J. Am. Chem. Soc. 1978, 100, 7746.
Me
Me
5-endo-dig
Ph
5-exo-dig
O
OH
Developing negative charge on the central allenic carbon is

in the same plane as the OMe group
HO
n
n = 1,2
Li
NaOMe
X
Ph
5-endo-trig
Ph
Ph
R = H, OMe
4-endo-dig
however, the acid catalyzed version does cyclize
J. Am. Chem. Soc. 1983, 105, 5090

J. Chem. Soc., Chem. Commun. 1982, 36.
Li
Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736.

Johnson, Can. J. Chem. 1990, 68, 1780
Li
Li
Ph
Rules for Ring Closure: SP Carbon & Related Systems
Digonal C yclizations: Interesting Examp les
Conclusions and Caveats

! Baldwin's Rules are an effective first line of analysis in
evaluating the stereoelectronics of a given ring closure
! Baldwin's Rules have provided an important foundation for the

study of reaction mechanism
! Competition studies between different modes of cyclization only
give information about relative rates, and are
not an absolute indicator of whether a process is "favored" or
"disfavored"
! Structural modifications can dramatically affect the cyclization
mode; beware of imines and epoxides
EXO
Trig
Dig
5
6
7
Dig
!
!
!
!
!
!
!
!
!
!
OTBS 1) RCOCl
2) AgBF4
Me
71%
N+
86%
Me
N+
CO
Works for varying ring sizes and R groups; acylnitrilium

ion can also work as an electophile in a Friedel-Crafts
type of reaction
5-endo-dig
! Livinghouse, Tetrahedron 1992, 48, 2209.
Trig
Tet
OTBS
LiCH2NC;
TBS-Cl
Me
ENDO
Tet
Chem 206
O
H
Me
R
N
O
Et3N, Toluene, reflux

12 h, 65-70% y.
MeO2C
CN
CN
5-exo-dig
O
! Trost, JACS 1979, 101, 1284
CO2Me
OH
HO2C
H
Hirsutic Acid C
D. A. Evans
Chem 206
Ethane Rotational Barrier: The FMO View

F. Weinhold, Angew. nature 2001, 411, 539-541"A New Twist on Molecular Shape"
One explanation for the rotational barrier in ethane is that better overlap is
possible in the staggered conformation than in the eclipsed conformation as
shown below.
In the staggered conformation there are 3 anti-periplanar CH Bonds
H
C
C
! CH
HOMO
!" CH
!* CH
LUMO
! CH
In the eclipsed conformation there are 3 syn-periplanar CH Bonds

H
!" CH
! CH
HOMO
!* CH
LUMO
! CH
Following this argument one might conclude that:
For purposes of analysis, each eclipsed conformer may be broken up

into its component destabilizing interactions.
Incremental Contributions to the Barrier.
Structure
! The staggered conformer has a better orbital match between bonding

and
antibonding states.
! The staggered conformer can form more delocalized molecular orbitals.
Eclipsed atoms " E (kcal mol -1)
J. P. Lowe was the first to propose this explanation
"A Simple Molecuar Orbital Explanation for the Barrier to Internal

Rotation in Ethane and Other Molecules"
J. P. Lowe, JACS 1970, 92, 3799
-1
ethane
3 (H!H)
+1.0 kcal mol
propane
2 (H!H)
1 (H!Me)
+1.0 kcal mol -1

+1.4 kcal mol -1
Me
Me
Me
Calculate the the rotational barrier about the C1-C2

bond in isobutane
D. A. Evans
Chem 206
Acyclic Conformational Analysis: Butane
Butane
The 1,2-Dihaloethanes
X
H
H
H
C
H
X = Cl; !H = + 0.91.3 kcal/mol

X = Br; !H = + 1.41.8 kcal/mol
X = F; !H = 0.6-0.9 kcal/mol
Observation: While the anti conformers are favored for X = Cl, Br, the gauche
conformation is prefered for 1,2-difluroethane. Explain.
Using the eclipsing interactions extracted from propane & ethane we should be
able to estimate all but one of the eclipsed butane conformations
staggered
conformation
Me
C
Me
H
H
H
H
H
eclipsed
conformation
!E=?
H
Me
Me
Discuss with class the origin of the gauche stabilization of the difluoro anaolg.
Recent Article: Chem. Commun 2002, 1226-1227 (handout)
Relationship between !G and Keq and pKa
Eclipsed atoms
! E (kcal mol -1)
1 (H"H)
2 (H"Me)
+1.0 kcal mol -1

+2.8 kcal mol -1
# E est = 3.8 kcal mol -1
! G = RT Ln K
Recall that:
or
! G = 2.3RT Log10K
The estimated value of +3.8 agrees quite well with the value of +3.6 reported
by Allinger (J. Comp. Chem. 1980, 1, 181-184)
2.3RT = 1.4 (!G in kcal Mol1 )
At 298 K:
n-Butane Torsional Energy Profile
! G298 = 1.4 Log10Keq

E1
pKeq = Log10Keq
Since
Hence, pK is proportional to the free energy change
energy
H
H
! G298 = 1.4 pKeq
1.0
10
100
pKeq
0
1
2
!G
0
1.4
2.8 kcal /mol
Me
Ref = 0
Me A
HH
C
C
H
Me
H
H
MeMe
Me
H
C
H
Keq
E2
+3.6
Me
Me G
+0.88
+5.1
Barrier?
Chem 206
Acyclic Conformational Analysis: Butane
D. A. Evans
Butane continued
From the torsional energy profile established by Allinger, we should be able to
extract the contribution of the Me"Me eclipsing interaction to the barrier:
Nomenclature for
staggered conformers:
Me
C
Me
Me
H
H
Me
! E = +5.1 kcal mol-1
eclipsed
conformation
H
H
sp
-60
Incremental Contributions to the Barrier.
1 (Me!Me)
15%
0
R
1 (Me!Me) = +3.1
+2.0
+3.1
15%
1 (Me!Me) = +5.1 2 (H!H)
2 (H!H)
gauche(-)
or g-
RR
2 (H!H) + 1 (Me!Me) = +5.1
" E (kcal mol
H
H
(Klyne, Prelog, Experientia 1960, 16, 521.)
Let's extract out the magnitide of the MeMe interaction
Eclipsed atoms
gauche(+)
or g+
70%
trans or t
or (anti)
Conformer
population
at 298 K:
Me
Me
Me
Me
staggered
C
conformation Me
Me
+60
sc
sc
ac
ac
-1)
-120
+120
ap
R
R
C
Eclipsed Butane
conformation
180
R
From the energy profiles of ethane, propane, and n-butane, one may extract
the useful eclipsing interactions summarized below:
C
R
Hierarchy of Eclipsing Interactions

Torsion angle
X
X
H
H
H
H
Y
H
H Me
Me Me
! E kcal mol
+1.0
+1.4
+3.1
-1
Designation
Symbol
n-Butane
Conformer
E2
Energy Maxima
0 30
syn periplanar
sp
Energy Minima
+60 30
+ syn-clinal
+ sc (g+)
+120 30
+ anti-clinal
+ ac
E1
180 30
antiperiplanar
ap (anti or t)
-120 30
- anti-clinal
- ac
E1
-60 30
- syn-clinal
- sc (g-)
Acyclic Conformational Analysis: Pentane
D. A. Evans
Chem 206
n-Pentane
Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -):
Me
Me
H
Me
g+t
Me
Me
Me
Me
tg-
H
g+g+
Me
H
g+g-
Me
Me
t,t
H
Me
Me
Me
Me
H
tg+
Me
H
g-g-
Me
H
Me
Me
g-t
g-g+
1,3(Me!Me) = + 3.7 kcal mol -1
Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions

Me
3.1
Me
Me
~ 3.7
Me
Me
Me
~3.9
Me
Me
~ 7.6
It may be concluded that in-plane 1,3(Me!Me) interactions are Ca +4

kcal/mol while 1,2(Me!Me) interactions are destabliizing by Ca 3 kcal/mol.
Chem 206
Acyclic Conformational Analysis: Natural Products
D. A. Evans
The syn-Pentane Interaction - Consequences
Lactol & Ketol Polyether Antibioitics

O
R
R'
Me
R'
Me
Me
Me
Me
R'
HO
Me
or
Me H H Me
H R R' H
tt
g-g-
Me
Me
Me
Me
O
OH H
Me
Me
OH
Me
O
H
Et
Me
O
Me OH Et
Et
OH
Ferensimycin B, R = Me
Lysocellin, R = H
R'
or
Me H H R'
H H R H
tg
gt
The conformation of these structures are strongly influenced by the

acyclic stereocenters and internal H-bonding
Consequences for the preferred conformation of polyketide natural products

Analyze the conformation found in the crystal state of a bourgeanic acid derivative!
Alborixin R = Me; X-206 R = H

Internal H-Bonding
R
Me
Me
OH
Me
OR
Me
Me
O
O
Me
Me
Me
OH
H
Me
OH
Me
OH
OH
OH
O
Me
Me OH
O
Et
Me
Me
OH
Bourgeanic acid
Metal ion ligation sites (M = Ag, K)

R
Me
Me
O
O
C
Me
Me
Me
Me
OH
H
Me
H
O
OH
OH
OH
O
Me
Me OH
O
Et
Me
OH
Chem 206
Conformational Analysis: Ionophore X-206/X-rays
D. A. Evans
X-ray of Ionophore X-206 - Ag+ - Complex
X-ray of Ionophore X-206 ! H2O

Internal H-Bonding
Me
Me
Me
O
Me
OH
H
Me
Metal ion ligation sites (M = Ag, K)
Me
OH
O
Me
H
O
OH
OH
OH
Me
O
Me
Me OH
O
Et
Me
OH
Me
O
O
C
Me
Me
Me
OH
H
Me
H
O
OH
"The Total Synthesis of the Polyether Antibiotic X-206". Evans, D. A.; Bender,
S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-2526.
Me
OH
OH
O
Me
Me OH
O
Et
Me
OH
Chem 206
Stabilized Eclipsed Conformations in Simple Olefins
D. A. Evans
Butane versus 1-Butene
Simple olefins exhibit unusal conformational

properties relative to their saturated counterparts
Me
staggered
conformation
Propane versus Propene

109
H
Me
C
H
120
" = 50
CH2
H
H
H
eclipsed
conformation
staggered
conformation
eclipsed
conformation
! G = 0.83 kcal mol-1
"=0
! = 50
CH2
! = 180
Me
+2.0 kcal/mol
H
C
H
H
H
C
H
H
H
H
C
H Me
K. Wiberg, JACS 1985, 107, 5035-5041

K. Houk, JACS 1987, 109, 6591-6600
H
H
stabilizing conjugation between

!"CX & #CH
+1.33
kcal
H
Me
+1.32 kcal
H
H
H
Me
H
H
C
C
H
New (de)stabilizing effect
The Torsional Energy Profile
!=0
Me
CH2
C
H
H
eclipsed
conformation
H
H
! G = +4 kcal mol-1
CH2
staggered
conformation
H
C
Me
Hybridilzation change opens up the CCC bond angle

! The Propylene Barrier
Me
Me
H
H
CH2
H
H
Me
H
C
H H
+0.49 kcal
H
H
! = 120
!=0
! = 180
Conforms to ab initio (3-21G) values:

Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
! Acetaldehyde exhibits a similar conformational bias

O
H
H
O
H
Me
H
O
H
H
H
O
Me
Me
H
Me
H
The low-energy conformation in each of above cases is eclipsed
D. A. Evans
Chem 206
The Gauche Effect
X
H
H
H
C
H
C
H
X = Cl; H = + 0.91.3 kcal/mol

X = Br; H = + 1.41.8 kcal/mol
X = F; H = 0.6-0.9 kcal/mol
Observation: While the anti conformers are favored for X = Cl, Br, the gauche
conformation is prefered for 1,2-difluroethane. Explain.
Discuss with class the origin of the gauche stabilization of the difluoro anaolg.
Recent Article: Chem. Commun 2002, 1226-1227 (handout)
-anti-bonding States: (CX)

CH3H
CH3CH3
CH3NH2
CH3OH
CH3F
Increasing -acceptor capacity
best acceptor
Your Thoughts on the trend shown below:

-anti-bonding States: (CX)

X
H
CH3F
CH3Cl
CH3Br
Increasing -acceptor capacity
H
H
best acceptor
H
C
X
X
X = Cl; H = + 0.91.3 kcal/mol

X = Br; H = + 1.41.8 kcal/mol
X = F; H = 0.6-0.9 kcal/mol
The Intramolecular Aldol Condensation
D. A. Evans
Cyclization of 1,4-Diketones: McCurry, J. Org. Chem. 1974, 39, 2316-2319

O
O
Me
5% NaOH,
The Model: The product-determining step is C-C bond formation to produce

A1 and A2. Steric hindrance at the electrophilic carbonyl center appears to
dictate the relative rates of cyclization.
R. N. Lacey, J. Chem. Soc 1960, 1639-1648
O
1
Me
Me
A2
Cyclization of 1,5-Diketones
P2 : P1 = 94 : 6
HO
OH
Chem 206
O
Me
Me
5% NaOH,
P2
OH
HO
Me
P1 O
P2
1. Enolization is fast relative to condensation (1 becones fully

deuterated, 1-d9 prior to the aldol event).
2. Indepentently formed adduct A1 does not revert to diketone 1.
Rather, it rapidly dehydrates to P1.
3. The overall reaction is kinetically controlled.
4. P1 is only very slowly converted into P2 (several days). Hence,
more evidence that system is not under thermodynamic control.
HO
HO
Me
OH
McCurry suggests that there overlap problems with the retro-aldol event.
HO
P1
X
O
The Retro-aldol Step: The base-induced retrol-aldol reaction is generally quite

competitive with dehydration. The MuCurry study points out the cyclopentanone
system is an exception where dehydration is fast relative to retroaldol. McCurry
states:
P2 : P1 = 94 : 6
P1
Equilibration
much faster than in the 5-membered
case
Me
Me
A2
R
P2
P2
Me
HO
5% NaOH,
P1
Me
HO
The following facts have been accumulated on this cyclization:
P2 : P1 = 20 : 1
Me
R
O
A1
These systems follow the same rules.

Protocol: Identify the least sterically hindered
C=O. Condensation will occur onto that center.
A1
D. A. Evans
Chem 206
! Problems of the Day:

Can you predict the stereochemical outcome of this reaction?

O
Chemistry 206
OTs
Me
EtO
n-C4H9
Lecture Number 5
OLi
LiNR2
Me
EtO
n-C4H9
OTs
98:2
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.

!
Conformations of Simple Olefinic Substrates
Introduction to Allylic Strain
Introduction to Allylic Strain-2: Amides and Enolates
OH
CH2OBn
O
Me
Me
B2H6
H2O2
"
"
O
Me
CH2OBn
Me
diastereoselection 8:1
Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 259.

A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860
Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
(handout)
F. Weinhold, Nature 2001, 411, 539-541
"A New Twist on Molecular Shape" (handout)
D. A. Evans
Wednesday,
September 28, 2005
Me
Me
Me
PhNCO
Et3N
"
Me
"
O
N
NO2
only one isomer
A. Kozikowski & Co-workers, Tetrahedron Lett. 1982, 23, 2081.
We call this
Allylic Strain
Chem 206
Stabilized Eclipsed Conformations in Simple Olefins
D. A. Evans
Butane versus 1-Butene
Simple olefins exhibit unusal conformational

properties relative to their saturated counterparts
Me
staggered
conformation
Propane versus Propene

109
H
Me
C
H
120
H
H
" = 50
CH2
H
H
H
eclipsed
conformation
staggered
conformation
eclipsed
conformation
! G = 0.83 kcal mol-1
"=0
! = 50
CH2
! = 180
Me
+2.0 kcal/mol
H
C
H
H
H
C
H
H
H
H
C
H Me
K. Wiberg, JACS 1985, 107, 5035-5041

K. Houk, JACS 1987, 109, 6591-6600
H
H

!"CX & #CH
+1.33
kcal
H
Me
+1.32 kcal
H
H
H
Me
H
H
C
C
H
New (de)stabilizing effect
!=0
Me
CH2
eclipsed
conformation
H
H
! G = +4 kcal mol-1
CH2
staggered
conformation
H
C
Me
Hybridilzation change opens up the CCC bond angle

! The Propylene Barrier
Me
Me
H
H
CH2
H
H
Me
H
C
H H
+0.49 kcal
H
H
! = 120
!=0
! = 180

! Acetaldehyde exhibits a similar conformational bias

O
H
H
O
H
Me
H
O
H
H
H
O
Me
Me
H
Me
H
The low-energy conformation in each of above cases is eclipsed
Evans, Duffy, & Ripin
2-propen-1-ol
1-butene
H
H
Me
E (kcal/mol)
E (kcal/mol)
Chem 206
Conformational Barriers to Rotation: Olefin A-1,2 Interactions
OH
0
-180
-90
90
180
0
-180
! (Deg)
-90
! = 50
H
C
H
H
H
C
Me
H
! = 60
H
C
+1.33
kcal
H
H
Me
+1.32 kcal
H
+0.49 kcal
C
H
H
H
OH
!=0
! = 120
!=0

OH
H
! = 120
H
H
! = 180
H
C
HO
H
!=0
C
H Me
! = 180
Me
H
180
! (Deg)
90
H
! = 180
C
HO
!=0
+1.18 kcal
C
H
+2.00
kcal
H
H
H
+0.37 kcal
! = 180
Conformational Barriers to Rotation: Olefin A-1,2 Interactions-2
Chem 206
2-methyl-1-butene
H
2-methyl-2-propen-1-ol
Me
Me
-90
90
Me
OH
-90
! = 180 H
H
H
C
! = 180
! = 60
Me
H
! = 110
H
C
Me
+1.39 kcal
Me
H
+0.06 kcal
H
H
H
C
OH
Me
Me
H
! = 120
!=0
180
HO
Me
C
90
Me
Me
! = 50
H
! (Deg)
!=0
0
-180
180
! (Deg)
C
H Me
0
-180
E (kcal/mol)
E (kcal/mol)
H
H
C
H
+2.68
kcal
OH
!=0
Me
C
H HO
H
! = 180
!=0
+1.16 kcal
H
C
Me
H
H
H
C
H
+2.01
kcal
Me
+0.21 kcal
! = 180
Conformational Barriers to Rotation: Olefin A-1,3 Interactions
(Z)-2-pentene
(Z)-2-buten-1-ol
Me
OH
0
-180
-90
90
0
-180
180
-90
180
90
! (Deg)
! (Deg)
C
H Me
Me
E (kcal/mol)
Me
E (kcal/mol)
Me
Chem 206
!=0
!=0
Me
C
H HO
H
C
! = 180
H
Me
+3.88 kcal
Me
H
!=0
! = 180
! = 90
Me
Me
H
C
Me
H
Me
H
+0.52
kcal
! = 180
Values calculated using MM2 (molecular mechanics) force fields

via the Macromodel multiconformation search.
OH
H
! = 120
OH
H
H
C
H
+1.44 kcal
H
C
C
H
+0.86
kcal
H
!=0
! = 180
Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841.
D. A. Evans
Chem 206
Acyclic Conformational Analysis: Allylic Strain
The Definition of Allylic Strain
Can you predict the stereochemical outcome of this reaction?

F. Johnson, Chem. Rev. 1968, 68, 375; Allylic Strain in Six-Membered Rings
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 (handout)
Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
OTs
Houk, Hoffmann JACS 1991, 113, 5006

R2
Consider the illustrated general structure

where X & Y are permutations of C, N, and O:
R3
EtO
3
Y
OLi
Me
LiNR2
R1
n-C4H9
R small
! Relevant enolate
R3
R2
R1
N
R large
R2
R1
N
R +
R large
R small
R small
Olefin
R large
R2
R1
N
O +
R small
Imine
In the above examples, the resident allylic stereocenter (!) and its associated
substituents frequently impart a pronounced bias towards reactions occuring at
the pi-bond.
Nonbonding interactions between the allylic

substituents (Rlarge, Rsmall) & substituents at
the 2- & 3-positions play a critical role in
defining the stereochemical course of such
reactions
A(1,2)
R2
R3
Y
2
(CH2)4OTs
TsO(H2C)4
Me
A1
R large
R small
interaction
OR
OR
Me
Bu
OLi
Bu
C
H
Bu
Me
OLi
H
Me
OR
TsO(H2C)4
C
Bu
OLi
Bu
C
Bu
OR
OLi
OR
Me
H
Me
HO
O
R
OBn
Hg(OAc)2
NaBH4
HO Me
R
OBn
M. Isobe & Co-workers, Tetrahedron Lett. 1985, 26, 5199.
(CH2)4OTs
A2
B2
C2
Representative Reactions controlled by Allylic Strain Interactions

HO
(CH2)4OTs
OR
C
C
OLi
C1 H
B1
H
Me
H
C
critical conformations
A(1,3)
interaction
R1
major
R large
Nitrone
Me
1
n-C4H9
R small
Imonium ion
98:2
EtO
conformations
R1
n-C4H9
Typical examples:
R2
Me
EtO
R large
X
2
OTs
EtO2C
Me
minor
n-C4H9
OLi
(CH2)4OTs
D. A. Evans
O
Me
LiNR2
n-C4H9
LiNR2
MeI
R-substituent
diastereoselection
R = Me
R = Et
87:13
80:20
R = CHMe2
40:60
Me
EtO
H
Ph
Ph
O
OBn
RO2C
LiNR2
Me
H
CO2Me
95% yield
OH
"one isomer"
Br
H
CO2Me
one isomer at C2
Me
I. Fleming & Co-workers, Chem. Commun. 1986, 1198.
RO2C
H
OBn diastereoselection 90:10 at C3
Me3Si
MeCHO
71% yield
MeO
LiNR2
Me3Si
major diastereomer opposite

to that shown

Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904.
MeO
OMe
n-C4H9
Me3Si
OMe
EtO
Me3Si
EtO
Ph
OM
NH4Cl
Me
n-C4H9
n-C4H9
Ph
OTs
EtO
Chem 206
Allylic Strain & Enolate Diastereoface Selection
Bn
G. Stork & Co-workers, Tetrahedron Lett. 1987, 28, 2088.
Me
Sn(OTf)2
Bn
RCHO
Boc
S
N
Boc
R
91-95%
S diastereoselection >95%
OH
T. Mukaiyama & Co-workers, Chem. Letters 1986, 637
TBSOCH2
Me CH2
Me CH2
LiNR2
MeI
TBSOCH2
"one isomer"
Me H
H
CO2Me
Me
OMe
Ph(MeS)2CLi
MeI
H
CO2Me
86%
PhMe2Si
OM
OEt
CO2Et
MeI
PhMe2Si
OEt
Me
R = Me: diastereoselection 99:1

R = Ph: diastereoselection 97:3
O
OMe diastereoselection 99:1
Me
K. Koga & Co-workers, Tetrahedron Letters 1985, 26, 3031.
Me
MeS
T. Money & Co-workers, Chem. Commun. 1986, 288.
MeS
MeS
OLi
R
O-t-Bu
KOt-Bu
THF -78 C
CO2Et
R = H: one isomer
CO2-t-Bu R = Me: > 15 :1

H
Y. Yamaguchi & Co-workers, Tetrahedron Letters 1985, 26,1723.
D. A. Evans
Chem 206
Allylic Strain & Olefin Hydroboration
! The basic process
Hydroborations dominated by A(1,3) Strain

S
S
H
OH
H2B
C
R
B2H6
OMe
OMe OH
B2H6
Me
Me
OH
Me
A
CH2
Me3C
Oxidant
Ratio, A:E
MCPBA
69:31
JOC, 1967, 32, 1363
BH3, H2O2
34:66
JOC, 1970, 35, 2654
Reference
OH
BnO
OH
Me
Me
B2H6
BnO
H2O2
Me
OH
Me
R2BH
major diastereomer
OH
RM
Me
R
R
control elements
H
H
RM
A(1,3) allylic strain

Steric effects; RL vs RM
Staggered transition states
Me
Me
Me
ThexylBH2,
Me
C
CH2OR
OH
TrO
OTr
OH
R2BH
Me
RL
H2O2
OH
TrO
H
H
RM
H
OH
OH
OH
Diastereoselection;
5:1
Me
Me
ThexylBH2,
Me
CH2OR
Me
OH
OH
OH
OTr
OH
OH
OH
OH
OTr
Diastereoselection;
Me
RL
OTr
then BH3 TrO
Me
R
See Houk, Tetrahedron 1984, 40, 2257
Me
Me
major diastereomer
OH
RM
Me
Me
TrO
then BH3
RL
Me
Me
C. H. Heathcock et. al. Tetrahedron Lett 1984 25 243.
RL
H2O2
Me
Diastereoselection = 3:1
OH
RL
OH
Me
! Acyclic hydroboration can be controlled by A(1,3) interactions:
RM
OH
H2O2
Me
Me
RL
Me
Me
Me
RM
CH2OBn
H2O2
Me
Me
CH2OBn
4: 1
Still, W.C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
OH
D. A. Evans
Consider the resonance structures of an amide:
O
R3
Chem 206
Allylic Strain & Amide Conformation
R1
R3
R1
C
N
+
R2
R3
R large
X
2
The selection of amide protecting group may be done with the knowledge that
altered conformational preferences may result:
R1
R small
A(1,3) interactions between the "allylic substituent" and the R1 moiety will
strongly influence the torsion angle between N & C1.
Me
C
N
Me
R C
R C
Ph
Favored
O
N
C
O
H
strongly favored
H
H
Me
N
R C
Me
O
R C
H
N
Me
Me
strongly favored
HCO2H
D. Hart, JACS 1980, 102, 397
O
Me
N
H
N
+ R
OM
base
favored
O
Me
Ph O
diastereoselection >95%
N
H
Me
L
H
(Z)-Enolate
H
H
O
H
N
Me L
OM
base
disfavored
O
H
N
Ph
H
H
HOCO
As a result, amides afford (Z) enolates under all conditions
" Problem: Predict the stereochemical outcome of this cyclization.

OH
A(1,3) interaction between the C2 & amide

C
R
substituents will strongly influence the torsion
N
angle between C1 & C2.
R
R
Quick, J. Org. Chem. 1978, 43, 2705
published X-ray structure of this amide shows chair

Me diaxial conformation
H R
Me
Disfavored
A(1,3)
Chow
Can. J. Chem. 1968, 46, 2821
N
+
! conformations of cyclic amides

C
Disfavored
Me
Favored for
R = COR
Favored
Me
Favored for
R = H, alkyl
identify HOMO-LUMO pair
N
Me L
N
Me
(E)-Enolate
D. A. Evans
Polypropionate Biosynthesis: The Acylation Event
A(1,3) Strain and Chiral Enolate Design

O
Me
O
N
O
LDA
O
Me
or NaNTMS2
Bn
enolization selectivity
>100:1
Bn
Me
N
H
JACS. 1982,104, 1737.

O
Me
SR
SR
Me
Me
Li
O
Et
O
!
Me
Cl
O
Me
Me
R
with M. Ennis JACS 1984, 106, 1154.
Diastereoselection ~ 97 : 3
El
N
Me
L
L
N
H
Me
Me
O
El
N
L
L
Why does'nt the acylation product rapidy epimerize at the exocyclic

stereocenter??
R
While conformers B and C meet the stereoelectronic requirement for

enolization, they are much higher in energy than conformer A. Further, as
deprotonation is initiated, A(1,3) destabilization contributes significantly to
reducing the kinetic acidity of the system
O
Me
H
N
R
R
favored
These allylic strain attributes are an integral part of the design criteria of
chiral amide and imide-based enolate systems
O
O
Me
Reduction
First laboratory analogue of the acylation event
! In the enolate alkylation process product epimerization is a serious

problem. Allylic strain suppresses product enolization through the
intervention of allylic strain
O
El
CO2
SR
Me
Bn
OH
SR
El
favored
enolization geometry
Acylation
O
N
HO
El(+)
Chem 206
Allylic Strain & Amide Conformation
CH2OH
Me
O
O
N
N
Bn
Evans
Tetr Lett. 1977, 29, 2495
Evans
JACS 1982,104, 1737.
Me
Me
N
Me
OH
Myers
JACS 1997, 119, 6496
X-ray structure
O
R
N
Me
R
R
Discodermolide
D. A. Evans
Chem 206
hinge
Me
O H
Me
Me
16
HO
O
Me
Me
Me
Me
17
Me
OH
OH
NH2
O
OH
- immunosuppressive activity
- potent microtubule-stabilizing agent
(antitumor activity similar to that of taxol)
The epimers at C16 and C17 have no or almost no biological activity.
The conformation about C16 and C17 is critical to discodermolide's biological activity.
S. L. Schreiber et al. JACS 1996, 118, 11061.
D. A. Evans
Conformational Analysis - Discodermolide X-ray 1

Me
HO
O H
Me
Me
Me
Me
Me
OH
Me
Me
OH
OH
NH2
O
Chem 206
Conformational Analysis - Discodermolide X-ray 2
D. A. Evans
Me
HO
O
O H
Me
Me
Me
16
Me
Me
Me
Me
OH
OH
NH2
O
OH
16
Chem 206
D. A. Evans
Conformational Analysis: Part3
Chem 206
Conformational Analysis of Cyclic Systems
Three Types of Strain:

Prelog Strain: van der Waals interactions
Chemistry 206
Baeyer Strain: bond angle distortion away from the ideal

Pitzer Strain: torsional rotation about a sigma bond
Baeyer Strain for selected ring sizes
Lecture Number 6
"angle strain"
size of ring Ht of Combustion Total Strain Strain per CH2
(kcal/mol) (kcal.mol) deviation from 10928'
(kcal/mol)
!
Conformational Analysis of C4 ! C6 Rings

A. Carey & Sundberg: Part A; Chapter 3
Eliel & Wilen, "Stereochemistry of Organic Compounds, "Chapter 11,
Configuration and Conformation of Cyclic Molecules, Wiley, 1994
Ribeiro & Rittner, "The Role of Hyperconjugation in the Conformational Analysis of
Methylcyclohexane and Methylheterocyclohexanes"
J. Org. Chem., 2003, 68, 6780-6787 (handout)
de Meijere, "Bonding Properties of Cyclopropane & their Chemical
Characteristics"
Angew Chem. Int. Ed. 1979, 18, 809-826 (pdf)
27.5
26.3
6.2
0.1
6.2
9.7
12.6
12.4
11.3
4.1
5.2
1.9
1.9
499.8
656.1
793.5
944.8
1108.3
1269.2
1429.6
1586.8
1743.1
1893.4
2051.9
2206.1
2363.5
3
4
5
6
7
8
9
10
11
12
13
14
15
2444'
944'
044'
-516'
9.17
6.58
1.24
0.02
0.89
1.21
1.40
1.24
1.02
0.34
0.40
0.14
0.13
Eliel, E. L., Wilen, S. H. Stereochemistry of Organic Compounds

Chapter 11, John Wiley & Sons, 1994.
! Baeyer "angle strain" is calculated from the deviation of the

planar bond angles from the ideal tetrahedral bond angle.
! Discrepancies between calculated strain/CH2 and the "angle
strain" results from puckering to minimize van der Waals or
eclipsing torsional strain between vicinal hydrogens.
Problem: Rationalize the regioselectivity of the following reduction
H
NaBH4
D. A. Evans
Friday,
September 30, 2005
O
OH
O
Stork, JACS, 1979, 7107.
Evans, Kim, Breit
Cyclopropane: Bonding, Conformation, Carbonium Ion Stabilization
Carbocation Stabilization via Cyclopropylgroups
Cyclopropane
H
H
! Necessarily planar.
! Subtituents are therefore eclipsed.
! Disubstitution prefers to be trans.
" = 120
! Almost sp2, not sp3
! = 3080 cm-1
Me
A rotational barrier of about

13.7 kcal/mol is observed in
following example:
Me
H
Walsh Model for Strained Rings:

! Rather than ! and !* c-c bonds, cyclopropane has sp2 and p-type
orbitals instead.
! (antibonding)
! (antibonding)
" (antibonding)
Nonbonding
Chem 206
side view
" (bonding)
" (bonding)
!1 (bonding)
de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics"
Angew Chem. Int. Ed. 1979, 18, 809-826 (handout)
de Meijere, A.; Wessjohann, L. "Tailoring the Reactivity of Small Ring Building
Blocks for Organic Synthesis." Synlett 1990, 20. (pdf)
NMR in super acids

!(CH3) = 2.6 and 3.2 ppm
Evans, Kim, Breit
Chem 206
Conformational Analysis: Cyclic Systems-2

Cyclobutane
145-155
Cyclopentane
H
H
ax
ax
eq
eq
! = 28
eq
eq
ax
ax
! Eclipsing torsional strain overrides

increased bond angle strain by puckering.
! Ring barrier to inversion is 1.45 kcal/mol.
H
H
H
H
H H
CsEnvelope
H
H
H
H
H H
H
H
H
H
CsEnvelope
C2 Half-Chair
! Two lowest energy conformations (10 envelope and 10 half chair conformations
Cs favored by only 0.5 kcal/mol) in rapid conformational flux (pseudorotation)
which causes the molecule to appear to have a single out-of-plane atom "bulge"
which rotates about the ring.
(MM2)
! Since there is no "natural" conformation of cyclopentane, the ring conforms to

minimize interactions of any substituents present.
H
H
CsEnvelope
(MM2)
H
H
! !G = 1 kcal/mol favoring R = Me equatorial

! 1,3 Disubstitution prefers cis diequatorial to
trans by 0.58 kcal/mol for di-bromo cmpd.
H H
! A single substituent prefers the equatorial position of the flap of the envelope
(barrier ca. 3.4 kcal/mol, R = CH3).
! 1,2 Disubstitution prefers
trans for steric/torsional
reasons (alkyl groups) and
dipole reasons (polar groups).
Me
Me
! 1,2 Disubstitution prefers trans diequatorial to
cis by 1.3 kcal/mol for diacid (roughly equivalent
to the cyclohexyl analogue.)
H H
! 1,3 Alkyl Disubstitution: Cis-1,3-dimethyl

cyclopentane 0.5 kcal/mol more stable than trans.
! A carbonyl or methylene prefers the planar position of

the half-chair (barrier 1.15 kcal/mol for cyclopentanone).
X
Evans, Kim, Breit
Methylenecyclopentane and Cyclopentene

Strain trends:
>
>
! Decrease in eclipsing strain

more than compensates for the
increase in angle strain.
Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2

center in the ring to minimize eclipsing interactions.
"Reactions will proceed in such a manner as to favor the formation or retention

of an exo double bond in the 5-ring and to avoid the formation or retention of
the exo double bond in the 6-ring systems." Brown, H. C., Brewster, J. H.;
Shechter, H. J. Am. Chem. Soc. 1954, 76, 467.
Examples:
H
O
NaBH4
k6
H
H
H H
H
H
OH
k6
= 23
k5
H
H H
NaBH4
k5
OH
Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.
hydrolyzes
13 times faster than
Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
O
OH
O
OEt
95.5:4.5 keto:enol
O
OEt
76:24 enol:keto
Brown, H. C., Brewster, J. H.; Shechter, H. JACS 1954, 76, 467.
Chem 206
"Total Synthesis of the Antifungal Macrolide Antibiotic (+)-Roxaticin," Evans, D. A.; Connell, B. T.
J. Am. Chem. Soc., 2003, 125, 10899-10905
Me
Me
Me
Me
OTBSO
22
18
Me
27
Me
Me
O
27
Me
22
18
XO
X = C(CH2)4
OH
OH
OH
OH
Me
PPTS, rt, MeOH.
63%
PPTS, rt, MeOH.
OX
12
Me
<10%
Me
O
OX
12
X = CMe2
OTBSO
Me
XO
OH
Me
27
Me2CH
22
16
HO
12
OH
Roxiticin
Me
hydrolyzes
13 times faster than
Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
Zaragozic Acid C Synthesis
OH
J. Leighton, J. Barrow
JACS 1994, 116, 12111-12112
CO2tBu
OBn
tBuO C
2
MgBr
CH2Cl2:THF
78 C
Ph
TBSO
Chelate Control
H
HO
76%
OH
CO2H OH
tBuO C
2
CO2tBu
OTBS
7
3
O
OBn
Ph
OTBS
OH
O
CO
H
2
HO
86%
HO2C
HO2C
3 steps
5
7
CO2tBu
OBn
tBuO C
2
OH
HO
HO
CO2H OH
O
H
91% 3 steps
tBuO C
2
OPMB
Li
Bn
CO2tBu OTBS
7
O
H
tBuO C
2
Me
65%
tBuO C
2
2 steps
70%
CO2tBu OTBS
7
5
O
H
tBuO C OBn
2
Ph
Me
tBuO C
2
CO2tBu OTBS
OH
Me
OR
Ph
O
H
tBuO C O
2
Ph
Bn
O
94%
OH
OAc
Me
0:10:1 CH2Cl2:TFA:H2O, 18 h
Me
R = PMB
Zaragozic acid C
R = Ac (89%)
HO2C
HO2C
HO
O
CO2H
3
Ph
4'
Me
Evans, Breit
Monosubstituted Cyclohexanes: A Values

R
!G = RTlnKeq
! Meaxial has 2 gauche butane interactions more than Meequatorial.

Expected destabilization: ! 2(0.88) kcal/mol = ~1.8 kcal/mol;
Observed: 1.74 kcal/mol
Me
Me
C
Me
H
C
H
H
H
R
A Values depend on the relative size of the particular substituent.
Keq
Chem 206
Me
H
AValue
Me
Me
1.74
Me
Me
Me
1.80
2.15
5.0
The "relative size" of a substituent and the associated A-value may not correlate.
For example, consider the CMe3 and SiMe3 substituents. While the SiMe3
substituent has a larger covalent radius, it has a smaller A-value:
! The A Value, or -!G, is the preference of the substituent for the

equatorial position.
Me
Me
C Me
Me
Me
AValue
Me
Si Me
4.5-5.0
Me
Sn Me
H
2.5
1.1
Can you explain these observations?
! The impact of double bonds on A-values:

Lambert, Accts. Chem. Res. 1987, 20, 454
R
H
H
substituent
!"G
R = Me
R = OMe
R = OAc
0.8
0.8
0.6
A-value
(cyclohexane)
1.74
0.6
0.71
The Me substituent appears to respond strictly to the decrease in nonbonding

interactions in axial conformer. With the more polar substituents, electrostatic
effects due to the trigonal ring carbon offset the decreased steric environment.
Evans, Breit
Impact of Trigonal Carbon
Polysubstituted Cyclohexane A Values
! Let's now compare look at the carbonyl analog in the 3-position

Me
H
H
Me
Chem 206
! As long as the substituents on the ring do not interact in either

conformation, their A-values are roughly additive
1,4 Disubstitution: A Values are roughly additive.
Me
!G = 1.36 kcal/mol
versus 1.74 for cyclohexane
Me
Me
!G = 0 kcal/mol
Me
Me
! Let's now compare look at the carbonyl analog in the 2-position

Me
Me3C
base
epimerization
H
Me
Me
!G = 2(1.74) = 3.48 kcal/mol
Me
Me3C
O
!G = 1.56 kcal/mol
1,3 Disubstitution: A Values are only additive in the trans diastereomer

X
However, the larger alkyl groups do not follow the expected trend.
Can you explain? (see Eliel, page 732)
CHMe2
base
epimerization
H
Me3C
Me3C
Me3C
Me
CHMe2
Me
Me
The new interaction!

For X = Me
H
CMe3
Me3C
O
!G = 1.62 kcal/mol
!G = A(Me) A(X)
Me
The cis Isomer
!G = 0.59 kcal/mol
base
epimerization
CMe3
Me
H
Me
Me
+ 0.88
H
Me
Me
!G = 2(.9) + 1(+3.7)= 5.5 kcal/mol

+ 3.7
+ 0.88
Evans, Breit
Let's now consider geminal substitution
Chem 206
Let's now consider vicinal substitution
Me
Ph
The prediction:
Me
Me
Ph
Case 1:
!G = A(Ph) A(Me)
Me
Me H
Me
The prediction:
!G = +2.8 1.7 = +1.1 kcal/mol
Observed:
!G = 1 gauche butane 2A(Me)

!G = +0.88 2(1.74) = +2.6 kcal/mol
!G = 0.32 kcal/mol
Observed:
!G = +2.74 kcal/mol
If the added gauche butane destabilization in the di-equatorial

conformer had not been added, the estimate would have been off.
Case 2:
Me
Me
OH
H
OH
Me
Me
The conformer which places the isopropyl group equatorial is much more
strongly preferred than would be suggested by A- Values. This is due to
a syn pentane OH/Me interaction.
Problem:
Can you rationalize the stereochemical outcome of this reaction?
O
O
EtO
n-C4H9
LiNR2
MeI
H
Me
EtO
n-C4H9
Evans, Breit
Heteroatom-Substituted 6-Membered Rings

! A-values at the 2-position in both the O & N heterocycles are larger than
expected. This is due to the shorter CO (1.43 ), and CN (1.47 ) bond
lengths relative to carbon (CC; 1.53 ). The combination of bond length and
bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4).
Reference:
Me
A-Values for N-Substituents in Piperidine

H
N
The Reference:
N
!G = 0.36 kcal/mol
Me
!G = 3.0 kcal/mol
Me
Chem 206
!"G = 1.74 kcal/mol
Me
! Hydrogen is "bigger" than the Nlone Pair.

Me
(1)
Me
!"G = 2.86 kcal/mol
Me
!"G = 1.43 kcal/mol
Me
!"G = 1.95 kcal/mol
Me
!"G = 2.5 kcal/mol
Me
!"G = 1.6 kcal/mol
Me
!"G = 1.9 kcal/mol
H
O
O
Me
(2)
H
H
Me
(3)
! The A-value of Nsubstituents is slightly larger than the corresponding

cyclohexane value. Rationalize
H
H
Me
(4)
N
Me
H
H
(5)
H
Me
(6) H N
H
H
Conformational Analysis: Bicyclic Ring Systems
Evans, Breit
Chem 206
Estimate the energy difference between the two methyl-decalins

shown below.
Me
Me
Hydrindane Ring System (6/5)

H
rigid
flexible
Decalin Ring System (6/6)

H
!G = 0.5 kcal/mol (at 23 C)

!G = 0.0 kcal/mol (at ~200 C)
mobile
rigid
! The turnover to favor the cis fusion results from the entropic preference for the
less ordered cis isomer.
The 5-5 Ring System

H
H
favored
2.4 kcal/mol
Relative !G
!G = +6.4 kcal/mol
Let's identify the destabilizing gauche butane interactions in the cis isomer
H
3
H
4
1
Me
Gauche-butane interactions
C1 ! C2
C1 ! C3
C4 ! C3
H
C
Me
A/B Trans
A/B Cis
"G(est) = 3(0.88) = 2.64 kcal/mol

Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid!
Conformational Analysis: Axial vs Equatorial Reactivity
Evans, Breit
Different reactivity for axial and equatorial substituents
! SN2 Reactions (Displacement with PhS)
Axial substituents are more hindered, thus less reactive in many

transformations
Me3C
0.13
H
OH
Me3C
OH
The axial diastereomer is not always slower reacting:
! Alcohol Oxidation with Cr(6+)
0.27
! Acid-catalyzed esterification
CO2H
CO2H
Me3C
CO2Et
H
CO2Et
20
k rel
3.2
H
Me
OH
Me
OH
Me
H
Me
3.36
The rate-determining step is breakdown of the chromate ester. This is an

apparent case of strain acceleration
0.05
! Ester Saponification
k rel
Me
0.04
H
Me3C
Me
Me3C
CO2H
CO2H
Me3C
OH
k rel
OH
H
Me3C
k rel
31
k rel
OH
OH
Me3C
Me3C
OTs
k rel
H
k rel
OTs
! Acetylation with Ac2O/Py
k rel
Chem 206
Me3C
For a more detailed discussion of this topic see:

Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic
Compounds pp 720-726
Conformational Analysis: Cyclohexanones
Evans, Hong, O'Brien
! Comparison of Calculated A Values and Experimental A Values

H
Me
H
Me3C
Me
Me3C
Method
Mol. Mechanics
(MMFF)
Semi-empirical
(PM3)
Lit.!G
!G (kcal/mol)
-1.6
-0.9
-1.8
Ph
H
H
Me3C
Ph
Me3C
Method
Mol. Mechanics
(MMFF)
Semi-empirical
(PM3)
Lit. !G
!G (kcal/mol)
-3.1
-4.7
-2.9
*Carey & Sundberg, Advanced Organic Chemistry: Part A, 3rd Ed.
! Calculated A Values for Substituted Cyclohexanones

CHMe2
base
epimerization
Me3C
Me3C
H
CHMe2
O
O
Method
Mol. Mechanics
(MMFF)
Semi-empirical
(PM3)
!G
(DAE)
!G (kcal/mol)
+0.2
-0.7
-0.59
CMe3
base
epimerization
Me3C
H
CMe3
Me3C
Method
Mol. Mechanics
(MMFF)
Semi-empirical
(PM3)
!G
(DAE)
!G (kcal/mol)
-2.7
-0.9
-1.62
Chem 206
D. A. Evans
Conformational Analysis: Part4
Chem 206
Problems of the Day:

Predict the stereochemical outcome of this reaction. The
diastereoselection is 99:1
Chemistry 206
mCPBA
Lecture Number 7
H
N
N
Ph
Ph
Martinelli, et.al. Tett. Lett. 1989, 30, 3935
Ground State Torsional Effects (Conformational Transmission)
Conformational Analysis of C6 ! C8 Rings continued
Transition State Torsional Effects
CurtinHammett Principle (Will not cover in lecture)
Rationalize the stereochemical outcome of this reaction.

Me
CO2Me
Me
Me
LiNR2
Me
Me-I
Me
Me
CO2Me
Me
diastereoselection is 8:1.
Ladner, et.al. Angew. Chemie, Int. Ed 1982, 21, 449-450
Eliel & Wilen, Stereochemistry of Carbon Compounds"

Chapter 11
Configuration and Conformation of Cyclic Molecules
Which is the more stable C=C isomer in the two THC structures?
Me
A. Carey & Sundberg: Part A; Chapter 4

"Study & Descrption of Reaction Mechanisms"
K. Houk, Science. 1986, 231, 1108-1117
Theory & Modeling of Stereoselective Organic Reactions (handout)
Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981(handout)
Me
OH
OH
Me
Me
Me
O
C5H11
Me
R. W. Kierstead, JACS 1967, 89, 5934
D. A. Evans
Monday,
October 3, 2005
C5H11
Conformational Analysis: Cylcoheptane
Evans, Breit
Cycloheptane
Chem 206
Cyclooctane
5
Chair-Boat
Lowest-energy conformation
7
eclipsed
1
Chair (2.16 kcal/mol)
Twist-Chair (0 kcal/mol)
Transannular strain
between C3 & C7
Ring strain originates in eclipsing interactions and transannular

vanderWaals interactions
Methylene position
!G
Boat (3.02 kcal/mol)
Twist-Boat (2.49 kcal/mol)
pseudoequatorial Me
1.8
pseudoaxial Me (kcal/mol)
2
2.8
3
>4.5
-0.3
6.1
Underside view of boat-chair C3 & C7 eclipsing interactions
Hendrickson, J. B. JACS 1961, 83, 4537.

See Eliel, page 762+
Olefins are preferentially orientated to eliminate eclipsing interactions.
1
3
Conformational Analysis: Cyclooctane
Evans, Breit
Chem 206
Cyclooctane continued...
5
Chair-Boat (BC)
Lowest-energy conformation
7
3
1
Transannular strain
between C3 & C7
Methyl position
!G
Chair-Boat (CB) conformation

reference structure
(pseudoeqatorial)
1.8
(pseudoaxial) (kcal/mol)
2.8
3
>4.5
-0.3
6.1
Chair-Chair (CC) conformation

(+11.6 kcal/mol)
Cyclooctane derivatives
Boat-Boat (BB) conformation

(>+ 8 kcal/mol)
O
Carbonyl is positioned at C3 or C7
Olefin is positioned at C3-C4 or C6-C7

Me
Me
Nu
LINR2
!
MeI
X
Disubstitution occurs at C4 or C6
Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
Me
Me
Nu
SN2 occurs at C1 and C5
Predict
stereochemistry
Me
LiCuMe2
Me
Predict
stereochemistry
Ground State Torsional Effects
D. A. Evans
Torsional Effects
Chem 206
Relevant Orbital Interactions:
Torsional Strain: the resistance to rotation about a bond
Torsional energy: the energy required to obtain rotation about a bond
Torsional Angle: also known as dihedral angle
Torsional steering: Stereoselectivity originating from transition state

torsional energy considerations
H
H
H
!"CX & #CH
# CH & ! electrons are

destabilizing
Dorigo, A. E.; Pratt, D. W.; Houk, K. N. JACS 1987, 109, 6591-6600.
G = +3 kcal mol-1
Conformational Preferences: Acetaldehyde
eclipsed
staggered
Torsional Strain (Pitzer Strain): Ethane
H
O
CH2
C
H
H
eclipsed
conformation H
CH2
staggered
conformation
H
H
H
H
The eclipsed conformation (conformation A) is preferred.

Polarization of the carbonyl decreases the 4electron destabilizing
Rotational barrier: 1.14 kcal/mol
Houk, JACS 1983, 105, 5980-5988.
+2.0 kcal/mol
Conformational Preferences
1-Butene (X = CH2); Propanal (X = O)
C
H
H
Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041.
A
See Lecture 5 for previous discussion
H
X
Me
H
Me
X
A'
H
X
Me
H
Conformation A is preferred. There is little steric repulsion between the

methyl and the X-group in conformation A'.
D. A. Evans
Ground State Torsional Effects: Conformational Transmission
Observation:
Relative enolate stability correlates to ring junction stereochemistry
Let ! be defined as the torsion or dihedral angle for butane

!
Me
H
base
O
LiO
ratio: 13 : 87
H
Let's now consider cyclohexane
base
H
LiO
real chair
! = 60
! = 56
CCC" 109 28'
!R = 56
!P
!R
!M
15
41
!M
56
44
11
!P
56
61
+6
["] = !R( 0) !R( 56)

Operation:
56
base
O
LiO
LiO
ratio: 92 : 8
56
How do we explain the experimental observations shown above?
15
56
56
H
["]
56
H
H
!R = 0
!O
ratio: 10 : 90
H
CCC" 111
Given cyclohexane with an identified torsion angle !R, if !R either increases

or decreases what effects in angle change are transmitted to !O, !M, and !P?
!O
LiO
Perfect chair
Observation:
Relative enolate stability seems to be correlated to position of C=C
!
C
LiO
House, JOC 1965, 30, 1341
C Me
ratio: 70 : 30
! = 60 for butane
B
H
LiO
A Me
Me
base
O
H
H
LiO
Chem 206
56
H2
44
61
0*
56
Hence, relative to cyclohexane, the following notation for torsion angle change
may be denoted:
11
+6
Readings: Velluz etal, Angew. Chemie, Int Ed. 1965, 4, 181-270 (pdf)
For !P
For !M
D. A. Evans
Ground State Torsional Effects: Conformational Transmission-2
Chem 206
Operation: trans-dimethylcyclohexane
H
Me
56
Me
56
64
Me
64
base
Me
Endocyclic dihedral angle is 56

Exocyclic dihedral expands correspondingly (+4): 64
LiO
H
R
56
cis-decalin
B
60 60
56 56
LiO
effects reinforcing
Me
Me
OH
B
R
Me
2) Ring B will resist increase in its ring fusion torsion angle
1) C=C will close down ring=B torsion angle
OH
Me
Me
O
C5H11
Me
C5H11
R. W. Kierstead, JACS 1967, 89, 5934
3) Therefore torsion effects are opposed
effects opposing
Question: Which is the more stable C=C isomer in the two THC structures?
1) C=C will open up ring=B torsion angle
ratio: 92 : 8
Which C=C bond isomer below is more stable?
LiO
56
Simple Application: Reinforcing Torsional Effects
base
Me
Me
trans-decalin
56
Me
effects reinforcing
effects opposing
Me
LiO
ratio: 10 : 90
Operation: cis-dimethylcyclohexane
56
Question: Which enol acetate is more stable?
2) Ring B will accomodate decrease in its ring fusion torsion angle
OBz
OBz
OBz
Ac2O
TSOH
3) Therefore torsion effects are reinforcing
or
O
AcO
AcO
Transition State Torsional Effects According to Houk
D. A. Evans
Chem 206
Houk: "Torsional effects in transition states are more important than in ground states"
Transition states
0
H
H2C
30
H*
C
H*
H2C
H2C
H
H-radical and H-anion: antiperiplanar !"CR orbital stabilized the TS

illustrated for Nu addition
H
C
RL
!C-Nu
homo
30 60 90 120
!"C-RL
lumo
!C-Nu
See lecture 5
+4.7
Forming bond
Forming bond
Same trends are observed for H+ addition

Houk, Science 1981, 231, 1108-1117
"The Theory and Modeling of Stereoselective Organic Reactions"
0
+2.4
Nu
0
+5.3
H-
Transition state
H
C
H
!"C-RL
!C-Nu
RL
30 60 90 120
Houk, JACS 1981, 103, 2438

Houk, JACS 1982, 104, 7162
!"C-RL
Nu
+1.6
H+
90
no H*
2 Kcalmol-1
H*
H
Ground state
Nu
!"C-RL
C
H
RL
!C-Nu
Transition State Torsional Effects: Olefin Additions
D. A. Evans
! Olefin Addition Reactions: Case one

How do we account for the high exo selectivities in
addition reactions to norbornene?
exo
H
Chem 206
! Olefin Addition Reactions: Case two

How do we account for the high selectilvities in the oxidation
of the indicated olefin?
Highly exo selective for electrophilic,

nucleophilic and cycloaddition reactions
OH
OH
O
OsO4
mCPBA
Rate enhancement due to strain

H
Ph
Ph
Ph
O
The Controversy over origin of high exoselectivities
endo
98 : 2
diastereoselectivity
99 : 1
diastereoselectivity
Nitrogen protecting group does not affect selectivities
Steric effects
Least nuclear motion
Orbital distortion
Schleyer: torsional steering
B
B
Favored
Martinelli, et.al. Tett. Lett. 1989, 30, 3935
Schleyer, P. R. J. Amer. Chem. Soc. 1967, 89, 701.
Addition from indicated olefin face avoids eclipsing A & B H's

Addition from exo face avoids eclipsing A & B hydrogens
(better hyperconjugative stabilization of transition state)
(better hyperconjugative stabilization of transition state)

Martinelli has carried out further studies on related structures...........
D. A. Evans
Transition State Torsional Effects: Olefin Additions
Martinelli: Torsional steering important in selectivity

O
mCPBA
H
89
99 : 1 diastereoselectivity
major
mCPBA
Me
Me
62
63
O
mCPBA
H
major
40
74
Authors propose that diastereoselection controlled by

TS torsional effects
Martinelli & Houk, J. Org. Chem. 1994, 59, 2204.
Chem 206
Cyclohexanone Addition Reactions: Hydride Reduction
D. A. Evans
Stereoselective Reductions: Cyclic Systems

[H]
Me3C
OH
Me3C
HA
OH
HE
Me3C
10
20
30
40
Attack Trajectories for Cyclohexanone

(Torsional Argument)
% Axial(-OH) Diastereomer
0
Nu:
Chem 206
50
60
70
80
90
HE
100
HA
LiAlH(Ot-Bu)3 92:8
Me
H B C CH2Me
H
M+
LiAlH4 93:7
This approach favored

sterically
The steric hindrance encountered by Nu-attack from the axial C=O face by the axial ring
substituents (hydrogens in this case) at the 3-positions is more severe than the
steric hinderance encountered from Nu-attack from the equatorial C=O face.
L-Selectride 8:92
K-Selectride 3:97
DIBAL-H 72:28
NaBH4 79:21
Nu:
Axial Attack
Observation: Increasingly bulky hydride reagents prefer to attack from

the equatorial C=O face.
H:
OCCHe dihedral:
+63.0
The most stereoselective Reductions
[H]
Me3C
OH
Me3C
Me3C
[H]
Reagent
Ratio
KBH(s-Bu)3
03 :97
Li in NH3
99 :01
Me3C
Steric Effects:
Ganem, Tet. Let 1981, 22, 3447

Hutchins, JOC 1983, 48, 3412
H
H
(R)
Reagent
R = Bn
R = Ph
LiBH(s-Bu)3
LiBH(s-Bu)3
Al/Hg/MeOH
Ratio
03 :97
01 :99
~90 :10
OCCHe dihedral:
56.0
The Issues Associated with the Reduction Process
Torsional Effects:
NHR Me C
3
H:
Equatorial Attack
NHR
private communication
OCCHe dihedral:
+4.0
NPh
Me3C
OH
Attack across equatorial C=O face sterically more favorable.

However, attack across the axial face of the C=O group avoids
development of eclipsing interactions in the transition state. (Note the
dihedral angle sign changes between reactants & products shown
above). These "torsional effects" favor axial attack.
Prediction
For "small" hydride reagents such as LiAlH4, torsional effects

are felt to be dominant and this explains the predisposition for
axial attack.
Prediction
For "large" hydride reagents such as HBR4, steric effects

now are dominant and this explains the predisposition for
equatorial attack.
D. A. Evans
Olefin Addition Reactions: Part1
Chem 206
! Problems of the Day: (To be discussed)

Rationalize the stereochemical outcome of these reactions.
Chemistry 206
OH
9-BBN
H2O2
Me2CH
Me
OH
Me2CH
Me
W. C. Still & J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487.
Lecture Number 8
Me
NHCONHPh
Olefin Addition Reactions1

!
Hydroboration
Epoxidation & Directed Epoxidation
Me
m-CPBA
Ph
NHCONHPh
Ph
CH2Cl2, 0 C
75 %
Roush, J. Org. Chem. 1987, 52, 5127.
Diastereoselection = 95 : 5
Problem 309. The indicated olefins were subjected to hydroboration/oxidation

as shown (Synlett, 1993, 696).

A. Carey & Sundberg: Part B; Chapter 4
"Electrophilic Additions to CC Multilple Bonds"
K. Houk, Science. 1986, 231, 1108-1117
Theory & Modeling of Stereoselective Organic Reactions (Handout)
K. Houk, Tetrahedron. 1984, 40, 2257-2274
Theoretical Studies of Stereoselective Hydroboration Reactions (Handout)
Me
Me
Me
Hoveyda, Evans, Fu, Chem Rev. 1993, 93, 1307-1370

Substrate-Directable Chemical Reactions
(Electronic Handout)
Wednesday,
October 5, 2005
Hexanes
Substrate A
*
OH
O
O
Me
Me
BH3THF
Me
Me
Substrate B
then H2O2
O
Me
Me
Me
BH3THF
Me
Me
Me
Hexanes
then H2O2
O
Me
D. A. Evans
OH
Me
*
OH
Me
OH
Part A. Please predict the major stereoisomer obtained from these reactions
and illustrate your predictions with clear 3D drawings.
Part B. Please also explain the fact that B suffers reductive ring opening while
A does not..
D. A. Evans
Olefin Addition Reactions: Introduction
Representative Cis-Addition Processes
Representative Trans-Addition Processes

! Halogenation
! Hydrometallation
R
C C R
H
H
Chem 206
M H
R C C R
H
H
M = B, Al, etc
R
C C R
H
H
Br
Br
H
R C C
H
Br
Br
! Hydrogenation
R
C C R
H
H
M-catalyst
H H
R C C R
H
H
! Group Transfer (epoxidation)

R
C C R
H
H
RO2H
ROH
R C C R
H
H
OsO4
N2
R2C=N2
N2
R C C R
H
H
R2
C
M-catalyst
+
! Cycloadditions (one of many!)

R
C C R
H
H
RO
R
H
C
C
R
H
HgOR
+ Hg(OR)2
! Oxysulfenation (M = S(II), Se(II)

R
C C R
H
H
RO
N2
Each process may proceed via an bridged

intermediate where X is the initiating electrophile
X
R C C R
H
H
! Addition of hydrogen halides
+ R2C=C=O
Attributes:
Olefin substitution may disrupt bridging
R C C R
H
H
R C C R
H
H
Attributes:
Each process adds to the C=C via a stereospecific process
Intermediates may be involved in some of the indicated reactions
H
R C C
H
SR
RSX
Os
! Group Transfer (cyclopropanation)

R
C C R
H
H
R
C C R
H
H
! Group Transfer (dihydroxylation)

R
C C R
H
H
! Oxymetallation (M = Hg(II), Tl(III)
R
C C R
H
H
+ HX
R C C
H
X
H C C
R
X
Attributes:
Process may proceed via an bridged
intermediate where H+ is the initiating electrophile
Olefin substitution, reaction conditions as well as
halide type may disrupt bridging
H
R C C R
H
H
D. A. Evans
The basic process

S
S
H B
H
H
R
Chem 206
H
H
R
OH
H2B
CH2OBn
!+ R
OMe
OMe OH
Me
Me3C
Ratio, A:E
MCPBA
69:31
JOC, 1967, 32, 1363
BH3, H2O2
34:66
JOC, 1970, 35, 2654
OH
O
Me Me Me
OH
Reference
OH
B2H6
H2O2
Me
Me
Response to steric effects: Here is a good calibration system:

Oxidant
BnO
OH
Me
Me
Me
B2H6
BnO
H2O2
OH
Me
OH
RM
RL
H2O2
Me
OH major diastereomer
RM
Me
Me
control elements
H
RM
major
H
H
Steric effects; RL vs RM
Staggered transition states
ThexylBH2,
OH
TrO
Me
OTr
Me
H
RL
H
H
H
CH2OR
Me
minor
Houk, "Theoretical Studies of Stereoselective Hydroboration Reactions"

Tetrahedron 1984, 40, 2257 (Handout)
Me
Me
Me
Me
TrO
then BH3
OTr
OH
OH
OH
Diastereoselection;
RM
CH2OR
RL
Me
Me
A(1,3) allylic strain
H
B
Me
C. H. Heathcock et. al. Tetrahedron Lett 1984 25 243.
OH
RL
Me
Acyclic hydroboration can be controlled by A(1,3) interactions:

B2H6
Me
Me
CH2
CH2OBn
H2O2
Me
Me
B2H6
ThexylBH2,
Me
Me
5:1
Me
Me
then BH3 TrO
TrO
OH
OH
OH
OTr
OTr
OH
OH
OH
OH
Diastereoselection;
4: 1
OH
Still, W.C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
D. A. Evans
Chem 206
! Case II: Dialkylboranes
R
Me
R2BH
H2O2
Me
RL
OH
Me
R2BH
H2O2
RM
RL
TS1
TS2
major
BH3
Me
RL
H2O2
TS1
Me
B
H
minor
TS2
minor
RM
RL
favored for R2BH
B
RM
H
Me
favored for BH3
Me
RL
H2O2
H
H
OH
H
RM
R2BH
H
! = 180 H C
H
M. M. Midland & Co-workers,

J. Am. Chem. Soc. 1983, 105, 3725..
Me
Me
OH
Me
! = 110
!=0
Me
+1.39 kcal
Me
H
+0.06 kcal
9-BBN
H2O2
Me
H
diastereoselection
borane methylsulfide
thexylborane
9-BBN
dicyclohexylborane
1:1
4:1
14 : 1
26 : 1
Me
H
C
H Me
CH2OH
Me
9-BBN
H2O2
OH
Me
Me
BH3
! = 50
!=0
RL
H2O2
CH2
RL
H
C
H
Me
R2BH
Representative Examples
Me
from Lecture 5:
OH
RM
RL
Midland finds that TS1 favored for R2BH reagents, but TS1 ~ TS2 for BH3
OH
RM
H
H
RL
Others have found that TS1 favored over TS2 for BH3
A(1,2) Strain
RM
Me
R2BH
H2O2
Me
RL
H
R
H
B
RM
Houk's rules: Orient RL anti-periplanar to incoming reagents to avoid TS eclipsing:
Me
OH
RM
! Case I: Borane
RM
major
R2BH structure is
a potential variable
RM
RL
B
H
H
C
H H
+2.68
kcal
OH
R
OH
R = n-Bu: diastereoselection 11:1

R = CHMe2: diastereoselection 24:1
Me
Model is consistent if you presume HO = RM: R = RL
Me
H
W. C. Still & J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487.

! = 180
! Case I: Dialkylboranes
H
TS1
Me
B
H
RM
major
! Case II: Borane

Me
R2BH
RL
H2O2
TS2
TS1
OH
H
RM
Me
minor
H
H
Me
R2BH
Me
RL
TS2
OH
major
H2O2
B
RM
RM
RL
RL
H2O2
OH
RM
RL
H
H
Me
BH3
favored for R2BH
B
RM
B
H
RM
RL
R
R
minor
Chem 206
D. A. Evans
Me
BH3
Me
RL
H2O2
OH
RM
RL
favored for BH3

OMe
Me
Me
Me
Me
Me
O
C
HO2C
OMe
O
OH H
OMe
Me
H
Me
D
O
Me H
E
O
Me
OMe
Lonomycin A
Evans, Ratz, Huff, Sheppard, JACS 1995, 117, 3448-3467.
F
Me
Me OH
C-9 ! C10
OMe
Me
O
BH3SMe2
85%
XP
Me
OMe
Me
O
Me
Me
O
OMe H
N
Me
O
OMe H
OH
10
9
Me
Me
Me
O
Me
XP
Me
O
OMe H
H
H
C
H
Me
RO
Me
B
H
OH
TS1 favored
10
9
Me
OH
R
H
H
Me
diastereoselection
> 95 : 5
H
H
H
RL
TS2 disfavored
R
Me
Bn
9-BBN
60%
H
H B
RO
H
C
H
RL
OMe
Me
OH
diastereoselection
92 : 8
10
OH
R
B
RO
H
Me
RL
TA1 disfavored
RO
Me
B
H
RL
TA2 favored
R
H
H
Represetative Hydroboration Examples: Acyclic Control
D. A. Evans
Me
For each of the examples shown below, attempt to rationalize the stereochemical
outcome of the reaction in terms of one of the models presented in the discussion.
CO2H
Chem 206
Me
1. 9-BBN
CH2
2. H2O2, NaOH
Me
Me
Me
OH
B2H6
Me
Et
O
Et
Et
Et
Et
H2O2
OH
Wolinsky, J.; Eustace, E. J.

J. Org. Chem. 1972, 37, 3376.
Et
R
Et
Me
CO2H
"one isomer"
O
2. H2O2, NaOH
Me
O
Me
Me
BH3.THF
Me
Me
OH
B2H6/[O]
Me
OH
CH2
OH
R
O
O
O
OBn
HO
CH3
Me
Me
BH3.THF
CH3
CH3
O
OBn
Me
CH3
R=H; Diastereoselection = 6.8:1

R=OBn Diastereoselection = 6.6:1
Oikawa et. al.

Tetrahedron Lett. 1983, 19, 1987.
OH
OH
B2H6/[O]
OH
Me
Me
B2H6/[O]
OH
OH
BH3.THF
Me
OH
CH2
OH
OH
H
Me
OH
CH2
Me
R
Me
HO
Me
Me
Me
Mori, K.
Tetrahedron 1976, 32, 1979
Wolinsky, J.; Nelson, D.

Tetrahedron. 1968, 25, 3767.
Me
Me
1. 9-BBN
CH2
Me
Me
Me
Me
Birtwistle et. al.

R = CH3;
Diastereoselction = 6.7:1
R = isopropyl "One Compound"
Me
OH
CH2
Schulte-Ette, K.H.; Ohloff, G.

Helv. Chim. Acta 1967, 50, 153.
B2H6/[O]
OH
Me
OH
Diastereoselection = 4.6:1
Representative Hydroboration Examples: Cyclic Systems
D. A. Evans
CH2
BH3.THF
BnO
HO
Me3C
Me3C
OH
H
O
OH
BH3.THF
Chem 206
OH
H
O
BnO
HO
Me
Me
B. Fraser-Reid et. al.

J. Am. Chem. Soc. 1984, 106, 731.
CH2
Me3C
BH3.THF
Me
Me
Me
CH3
H
N
Me3C
BH3.THF
CH2
O
BH3.THF
OH
Me3C
Me
Sallay, S. I.
J. Am. Chem. Soc. 1967, 89, 6762.
CH3
H
N
CH2
Major isomer; no ratio given.
OH
Me3C
Me
H
OH
OH
90% yield, no diastereoselection given
Me
Me
CH2
Me3C
BH3.THF
OH
Me3C
Me
Me
Me
CH2
BH3.THF
O
H
CO2Me
Me
Me
Y. Senda et. al.
Tetrahedron 1977, 33, 2933.
Me
(Compare with H.C. Brown's
case, with 9-BBN; 1.5:1)
Me
CH2
Ley, S. et.al.
J. Chem. Soc. Chem. Commun. 1983 630.
OH
Me
BH3.THF
O H
H
CO2Me
55% yield with the diastereomeric alcohol

produced in an unspecified amount.
Recycling of the minor isomer further
provided 15% of the desired material
NNHAr
Me
BH3.THF
Me
OH
NNHAr
Me
Me
McMurry, J. E.
J. Am. Chem. Soc. 1968, 90, 6321.
Me
OH
Minor diastereomer not detected
Directed Reactions: An Introduction
D. A. Evans
Chem 206
Stereochemical Control Elements for all reactions
Heteroatom-directed Reactions
Mechanism-based: (HO & C=C must be allylic)
! Steric & Electronic Factors

! Stereoelectronic Considerations
[3,3]
! Associative Substrate-Reagent Interactions
R
OH
! Steric control:
A B
CH2
C
H
via Reagent Ligation
H
Et2Zn
favored
A B
favored product
CH2I2
R
OH
CH2
R
O
Nonbonding Interactions disfavor the syn diastereoface
MCPBA
! Associative Substrate-Reagent Interactions
Cl
CO3H
A B
Henbest
J. Chem. Soc. 1958, (1957)
favored
A
C
B
favored product
Noncovalent Interaction favors the syn diastereoface
t-BuOOH
VO(acac)2
OH
OH
ratio 98 : 2
Sharpless
JACS 95, 6136, (1973)
disfavored
A B
Directed Oxidations
OH
ratio 90 : 10
Epoxidation
Hydroboration
Directed Reductions
Me
Hydrogenation
Hydride reduction
Directed CC Bond Constructions
CH2
Et2Zn
CH2I2
Agenda
Simmons-Smith Reaction
ratio 92 : 8
A B
A B
OH
Hydroxyl-directed Reactions
Review: Hoveyda, Evans, Fu Chem. Reviews 1993, 93, 1307
Zn
CH2I
Directed Reactions
Claisen Rearrangement
R
A
disfavored
A B
OH
Me
M(I) + H2
OH
Winstein
JACS 91, 6892, (1969)
(Ir+) Stork
JACS 105, 1072 (1983)
(Rh+) Evans
JACS 106, 3866 (1984)
Directed Reactions: An Introduction
D. A. Evans
The Directed Peracid Epoxidation
Orientation of the Directing Group
" Transition State Hydrogen Bonding: Substrate as H-bond donor
H
H
(Henbest)
reagent
Me
Me
Me
Me
OH
X = O, CH2
OH
!maj
Me
C
Reag
Me
OH
C
H
C
OH
!min
Me
TSminor
TSmajor
H
O
C
H2
t-BuO2H, V
RCO3H
CH2I2, ZnCu
! Estimate
71 : 29
95 : 5
> 99 : 1
O
!
~ 50
~ 120
O
C
H2
C
H2
H
O
C
H2
C
C
C
H2
!
O
H
CF3
C
C
O
H!
C
H2
C
H
require more acidic peracid both allylic alcohols and ethers OK
?
OH
Syn : Anti
(m-CPBA)
24 : 1
Syn : Anti
(CF3CO3H)
OTBS
Syn : Anti
(CF3CO3H)
1:7
5:1
1:8
12 : 1
1:4
1:6
OTBS
24 : 1
100 : 1
Me3C
Me3C
OH
OTBS
5:1
Me3C
Syn : Anti
(m-CPBA)
50 : 1
OH
The transition state bite angles for the above reactions are either
not known or have been only crudely estimated.
The "best guesses" are provided.
O H
R!
C
CF3
+5
H
O
" Transition State Hydrogen Bonding: Peracid as H-bond donor (Ganem)
Orientation of directing group is not the same for all reactions
Selectivity
require allylic or homoallylic alcohol
CF3
Reagent
!
O
R
Reag
O
!
R
O
Me
Chem 206
100 : 1
Me3C
Ganem Tet. Let. 1985, 26, 4895
Chem 206
Diastereoselective Peracid Epoxidation
D. A. Evans
Epoxidation of Cyclic Olefins with Amide &Urethane Directing Groups

Substrate
Major Product
HN
Me
HN
HO
Selectivity
Major
Product
Substrate
OH
Me
HO
HO
Epoxidation of Cyclic Homoallylic Alcohols
"highly
selective"
Me
OH
O
Me
OH
HN
O
Ph
HN
HO
Ph
Me
Et
Me
"highly
selective"
"highly
selective"
HO
Et
9:1
OH
HO
O
Selectivity
O
Me
Me
16 : 1
O
O
HO
O
R
a. R = NH2
b. R = NHBn
c. R = NMe2
Me
Me
R
RO
AcO
Me
Me
10 : 1
1:1
HO
HO
Me
a. R = OCONHBn
>20 : 1
b. R = OCONMe2
>20 : 1
O
Me
21 : 1
HO
HO
HOH2C
a. R = CONH2
5:1
O
RO
AcO
3:1
HO
O
HOH2C
6:1
b. R = CONHBn
>10 : 1
c. R = CONMe2
2:1
Conditions: Perbenzoic acid, or meta-chlorobenzoic acid in benzene.
(Table 11, p1316, from the Evans, Hoveyda, Fu review article)
5:1
AcO
AcO
Conditions: Perbenzoic acid, or meta-chloroperbenzoic acid

in benzene or cyclopentane.
(Table 14, p1318, from the Evans, Hoveyda, Fu review article)
The Sharpless Epoxidation
! The literature precedent: Sheng, Zajecek, J. Org. Chem. 1970, 35, 1839
OR
RO
O
V
Chem 206
Sharpless Epoxidation (V+5)
D. A. Evans
O+
O
!
RDS
RO
HO
O
!
TBHP
OR
RO
O
O
!
Catalyst
ROH
ROOH
HO
O
!
OH
O
!
HO
OH
OH
VO(acac)2
Mo(CO)6
O
"
4:1
1:1
! Next step: Sharpless, Michaelson JACS 1973, 95, 6136
OR
RO
O
V
O
"
80 oC
OH
OR
OH
Me
VO(acac)2
TBHP
Me
O
"
Me
80 C
Me
Me
Regioselection 20:1
Me
Aldrichimica Acta, 12, 63 (1979)

OH
OH
Mo(CO)6
Stereoselection 98:2
(90 % yield)
TBHP
OC2C3C4 = 41
The Sharpless estimate: ~50
80 C
O
"
Relative Rates (Diastereoselectivities) for the Epoxidation of

Cyclohexene Derivatives JACS 1973, 95, 6136
t-BuOH
t-BuOOH
Substrate
HO
HO
2
1
OR
tBu
3
RO
4
O
V
O
O
O-OtBu
V
O
krela,b (diastereoselectivityc )
peracid
Mo(CO)6
VO(acac)2
1.00
1.00
1.00
0.55 (92 : 8)
4.5 (98 : 2)
>200 (98 : 2)
OH
OAc
0.046 (37 : 63) 0.07 (40 : 60)
--
tBu
Chem 3D Transition State
OH
slow
RO
V
O
O
0.42 (60 : 40)
11.0 (98 : 2)
10.0 (98 : 2)
a,b The relative rate data apply only to a given column.
Values in parenthesis refer to the ratio of syn:anti epoxide.
Epoxidation of Acyclic Alcohols
D. A. Evans
Chem 206
! Allylic Alcohols:
OH
Me
OH
Me
Me
OH
Reagent
Me
Me
O
"
"
O
Reagent
~ 120
40-50
m-CPBA
t-BuOOH / VO(acac)2
t-BuOOH / Mo(CO)6
CH
Me
OH
H
C
Me
Me
TSminor
t-BuOOH
R2
Ratio
64 : 36
29 : 71
62 : 38
t-BuOOH / (t-BuO)3Al
64 : 36
VO(acac)2
R1
!
O
OH
R2
Me
H
SiMe3
R2
Yield
Ratio
H
C5H11
Bu
84 %
70 %
99 : 1
99 : 1
Me
Me
Me
!
O
VO(acac)2
60 %
EtO
OEt
O
Me
OH
OH
t-BuOOH
HO
OH
Me
Me
Me
OH
Reagent
Me
O
!
only isomer
Me
OEt
Me
!
O
VO(acac)2
60 %
EtO
OEt
Me
Me
Me
threo
O
!
OH
Me
Me
erythro
Reagent
m-CPBA
t-BuOOH / VO(acac)2
t-BuOOH / Mo(CO)6
Ratio
95 : 5
86 : 14
95 : 5
100 : 0
only isomer
Depezay, Tetrahedron Lett. 1978, 19, 2869.
Me
O
!
Me
VO(acac)2
60 % HO
OH
HO
t-BuOOH
OH
Boeckman, JACS 1977, 99, 2805.
K. B. Sharpless & Coworkers

R2
R1
Me
H TSminor
H
OEt
EtO
K. Oshima & Coworkers

Tetrahedron Lett. 1980, 21, 1657, 4843.
O
!
OH
O
EtO
Me
R1
SiMe3
OH
Me
Me
Me
Me
O
!
t BuOOH
HO
Me
Me
Reagent
m-CPBA
t-BuOOH / VO(acac)2
t-BuOOH / Mo(CO)6
Oshima, Tetrahedron Lett. 1982, 23, 3387.
OH
OH
SiMe3
OH
Me
O
!
OH
! V(+) Transition States: ! ~ 45

H
95 : 5
71 : 29
84 : 16
R1
Me
Ratio
Me
TSmajor
Me
erythro
! Estimate
TSmajor
Me
Me
threo
! RCO3H Transition States: ! ~ 120
OH
Reagent
OH
Me
NHCONHPh
Ph
m-CPBA
CH2Cl2, 0 C
75 %
Roush, J. Org. Chem. 1987, 52, 5127.
Me
NHCONHPh
Ph
O
!
Me
NHCONHPh
Ph
O
!
Chem 206
Epoxidation of Acyclic Homoallylic Alcohols
D. A. Evans
Anti diastereomer
Homoallylic Alcohols (Mihelich, JACS 1981, 103, 7690)
OH
t-BuOOH
OH
Me
O
!
+
OH
VO(acac)2
90 %
Me
O
!
Me
Me
Me
R1
Me
Me
Diastereoselection > 400 : 1
Control Elements
A(1,3) Strain
Directed Rxn
H
O
H
Me
HV
L'
O R
O
!
O H
!
R1
O
!
t-BuOOH
Me
Me
VO(acac)2
Et
Me
Et
Diastereoselection 12 : 1
Control Elements
Directed Rxn
Me
OH
H
O
L'
O R
HV
O
! H
OH
Ratio
C6H13
Me
Me
92 %
97 %
104 : 1
> 400 : 1
i-Pr
O
!
Me
Et
Et
R1
VO(acac)2
R2
Me
R1
Me
R1
R2
Yield
Ratio
C6H13
Me
Me
Me
73 %
70 %
70 : 1
85 : 1
81 %
16 :1
Me
C5H11
OH
t-BuOOH
C5H11
OH
O
!
R2
!O
Me
Me
OH
t-BuOOH
Me
Et
Me
Yield
VO(acac)2
OH
O
!
R1
R2
O
!
R2
OH
R2
Me
R1
OH
Me
Me
OH
R1
Syn diastereomer
HO
Me
R2
VO(acac)2
OH
O
!
t-BuOOH
R2
OH
OH
O
!
!O
Me
Me
Me
C5H11
Me
H
R2
O
R1
H
HV
L'
O R
! H
O
Me
Anti diastereomer
Anti should be more

diastereoselective
than syn
Product
Substrate
R2 H
O
R1
HV
L'
O R
O H
!
Me
OH
OH
2:1
!O
4.6 : 1
Me
Me
Me
Me
OH
Hex
!O
OH
OH
Syn diastereomer
Selectivity
Me
Me
OH
R
R = (CH2)7CO2Me
C5H11
E. D. Mihelich & Coworkers

J. Am. Chem. Soc. 1981, 103, 7690.
Epoxidation of Homoallylic Alcohols with TBHP, VO(acac)2
Prediction
OH
Hex
!O
1.4 : 1
D. A. Evans
Epoxidation & Cyclization of Bishomoallylic Alcohols
Bishomoallylic Alcohols (Kishi, Tet. Lett. 1978, 19, 2741)

R
OH
Me
t-BuOOH, VO(acac)2
CHMe2
C6H6, RT
Et
Et
Me
CHMe2
iPr
OH
VO(acac)2
OH
O
!
Chem 206
Me
iPr
OH
Et
Me
CO2H
O
!
OH
O R
Me
Et
Me
C6H6, RT
Me
CHMe2
Et
Me
Me
Et
Et
Et
OH
!
OH
Me
Ar = p-MeOPh
Ar
TBHP
AcOH
OH
Et
VO(acac)2
Et
B
Me
Me
Et
Ar
OH
O
!
t-BuOOH, VO(acac)2
CHMe2
HO
Me
OH
Me
Me
O
!
Me
OH
Et
iPr
Me
The Kishi Lasalocid Synthesis (JACS 1978, 100, 2933)

Me
AcOH
O
!
Et
diastereoselection ~ 9 : 1
H
Et
Et
Diastereoselection 8:1
OH
!
Et
Me
Me
H
Evans X-206 Synthesis JACS 1988, 110, 2506.
Et
Me
2nd stereocenter
is reinforcing
Me
Me
H
O
R
O
!
OH
O R
Me
Me
Me
O
!
Et
OH
Me
O
Me
OH
Me
Me
OH
Me
H
E
O
O
F
Me OH Me
O
D
OH
OH
Me
Et
OH
Me
t-BuOOH, VO(acac)2
CHMe2
Et
C6H6, RT
Me
OH
O
!
Me
Me
CHMe2
Et
Me
Me
R
H
O
Ph
OH
N
O
Et
OBn
Me
VO(acac)2
TBHP
C6H6, RT
O
!
Et
OBn
Me
HOAc
O
Me
Et
Me
O
!
O R
OH
XN
Et
Me
OH
OH
O
!
diastereoselection 20 : 1
(89 %)
D
O
XN
OBn
Et
Me
OH
!
2005 Nobel Prize in chemistry

to France's Yves Chauvin and
Americans Robert H. Grubbs
and Richard R. Schrock for
the development of the
metathesis method in organic
synthesis.
D. A. Evans
Chem 206

Rationalize the stereochemical outcome of the indicated reaction.
Me
Chemistry 206
MH
Me
H Me N
Sharpless Epoxidation continued.....
Hydrogenation
Problem 579. The following publication (J. Org. Chem. 1991, 56, 5553) reported the
surprisingly selective olefin epoxidation illustrated below. In this reaction, olefin B in 1
was found to be much less reactive than olefin A. Using your knowlege of
stereoelectronic effects, provide an explanation for the reduced reactivity of olefin B in
diene 1.
Cl
H
RCO3H

Hoveyda, Evans, & Fu (1993). Substrate-directable chemical reactions. Chem.
Rev. 93: 1307-70 (pdf)
J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (Handout)
97 : 3
28 : 72
R2AlH
LiAlH4
R. Noyori
Bull. Chem. Soc. Japan 47, 2617, (1974)
Cl
! Olefin Bromination
OH
Lecture Number 9
OH
2
favored
Cl
RCO3H
B
3
disfavored
Problem 313. Overman and co-workers recently reported the indicated selective
epoxidation in conjunction with a synthesis of briarellins A and E, a new family of
diterpenes (JACS 2003, 125, 6650). It should be noted that the Al(t-BuO)3/(t)-BuOOH
reagent system is both highly diastereoselective and site selective. It is also relevant to
the mechanism of the reaction that the ring-trisubstituted olefin lacking an allylic oxygen
substituent would normally be more prone to epoxidation with a peracid than the acyclic
trisubstituted olefin.
Me H
Investigation of the early Steps in Electrophilic Bromination through the

Study of the Reaction of Sterically Encumbered Olefins
R. S. Brown, Accts. Chem. Res. 1997, 30, 131 (handout)
TIPSO
H
Me H
H. Yamamoto et.al, Angew. Chem. Int. Ed. 2005, 44, 4389-4391 (pdf)
D. A. Evans
t-BuOOH
4 sieves
toluene, -20C
Me
Al(t-BuO)3
H
Me H
O
"
H
O
"
H
HO
Friday,
October 7, 2005
Me
H
H
HO
Part. Provide a general mechanism illustrating how the Al(t-BuO)3/(t)-BuOOH

reagent epoxidizes olefins. Three-dimensional drawings are recommended.
Part B. Provide a general mechanism illustrating how the above epoxidation
proceeds and provide the stereochemistry (") of the product epoxide along with a
stereochemical analysis of the noted face selectivity.
K. A. Beaver, D. A. Evans
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48.
Leading References:
Chem 206
Conformational Analysis and Reactivity: Curtin-Hammett Principle

Case 1: "Kinetic Quench"
J. I. Seeman, Chem Rev. 1983, 83, 83-134.

See also Eliel, pp. 647-655
k1, k2 >> kA, kB: If the rates of reaction are faster than the rate of
interconversion, A and B cannot equilibrate during the course of the
reaction, and the product distribution (PB/PA) will reflect the initial
composition.
How does the conformation of a molecule effect its

reactivity?
[PB]
=
[PA]
[B]o
[A]o
Consider the following example:

N
Me
Me
13 MeI
!GAB
Energy
13 MeI
!G1
!G2
PA
Do the two different conformers react at the same rate, or different

rates? What factors determine the product distribution?
PB
!G
Rxn. Coord.
The situation:
In this case, the product distribution depends solely on the initial

ratio of the two conformers.
Consider two interconverting conformers, A and B, each of which can

undergo a reaction resulting in two different products, PA and PB.
PA
k1
major
kA
kB
k2
steric
hindrance
less stable
PB
(1)
Me
Me
Me
H
N
We'll consider two limiting cases:

(1) The rate of reaction is faster than the rate of conformational interconversion
(2) The rate of reaction is slower than the rate of conformational interconversion
If the rates of conformationall interconversion and reaction are comparable, the
reactants are not in equilibrium during the course of the reaction and complex
mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83 - 144 for
analytical solutions.
!G = -3.0 kcal/mol
(ab initio calculations)
MeBr
Me
Me N
minor product
O
Me
more stable
H
O
-78C
minor
MeBr
Me
Me
H
Me N
Me
major product
While enolate conformers can be equilibrated at higher temperatures, the products of

alkylation at -78 C always reflect the initial ratio of enloate isomers.
Padwa, JACS 1997 4565
Chem 206
Curtin - Hammett: Limiting Cases
Case 2: Curtin-Hammett Conditons
k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of
interconversion, (!GAB is small relative to !G1 and !G2), then the ratio of
A to B is constant throughout the course of the reaction.
To relate this quantity to !G values, recall that !Go = -RT ln Keq or Keq =
e-!G/RT, k1 = e-!G1/RT, and k2 = e-!G2/RT. Substituting this into the above
equation:
[PB]
k1
PA
kA
kB
slow
k2
(1)
PB
slow
[PA]
k2
k1
!!G
[PB]
[PA]
Energy
!GAB
!G2
k2[B]
k1[A]
or
d[PB] =
k2[B]
k1[A]
d[PA]
(2)
Since A and B are in equilibrium, we can substitute Keq =
d[PB] =
k2
k1
= e-(!G2 + !G-!G1)/RT or
[PB]
[PA]
e-!!G/RT
Within these limits, we can envision three scenarios:
d[PB]
d[P ]
Using the rate equations dt A = k1[A] and dt = k2[B] we can write:
d[PA]
(4)
minor
Rxn. Coord.
The Derivation:
d[PB]
(e-!G/RT) = e-!G2/RTe-!G/RTe!G1/RT
Curtin - Hammett Principle: The product composition is not solely

dependent on relative proportions of the conformational isomers in
the substrate; it is controlled by the difference in standard Gibbs
energies of the respective transition states.
PB
!G
major
e-!G1/RT
Where !!G = !G2+!G-!G1
A
PA
e-!G2/RT
Combining terms:
fast
!G1
Keq =
Keq d[PA]
Integrating, we get
[PB]
[PA]
[B]
[A]
k2
K
k1 eq
When A and B are in rapid equilibrium, we must consider the rates of

reaction of the conformers as well as the equilibrium constant when
analyzing the product ratio.
(3)
If both conformers react at the same rate, the product distribution will
be the same as the ratio of conformers at equilibrium.
If the major conformer is also the faster reacting conformer, the
product from the major conformer should prevail, and will not reflect the
equilibrium distribution.
If the minor conformer is the faster reacting conformer, the product
ratio will depend on all three variables in eq (2), and the observed
product distribution will not reflect the equilibrium distribution.
This derivation implies that you could potentially isolate a product
which is derived from a conformer that you can't even observe in the
ground state!
Tropane alkylation is a well-known example.
Enantioselective Lithiation:
Me
Me
Chem 206
Some Curtin-Hammett Examples
N
N
less stable
more stable
i-Pr2N
i-Pr2N
s-BuLi
(-)-Sparteine
Me
13 MeI
faster
Li
Me
slower
13 MeI
Because sparteine is
chiral, these two
complexes are
diastereomeric and
have different
properties.
(-)-Sparteine
13Me
+ Me
N
Me +
N
13Me
minor product
major product
i-Pr2N
i-Pr2N
Lisparteine
Lisparteine
Me
Me
The less stable conformer reacts much faster than the more stable
conformer, resulting in an unexpected major product!
JOC 1974 319
faster
i-Pr2N
Oxidation of piperidines:
Cl
slower
i-Pr2N
Me
N
less stable
Me3C
Me3C
H
slower
Me
minor product
Enantioselectivities are the same, regardless of whether or not the starting material is
chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine
results in racemic product.
N+
O
Me3C
82 - 87% ee
k2 faster
H2O2
N
+ Me
Me3C
H
Ratio: 5 : 95
Me
more stable
Keq = 10.5
k1
Me
Me
major product
When the equilibrium constant is known, the Curtin-Hammett derivation

can be used to calculate the relative rates of reaction of the two
conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio
k2/k1 ~ 2.
Note that in this case, the more stable conformer is also the faster reacting conformer!
Tet. 1972 573

Tet. 1977 915
Note that the two alkyllithium complexes MUST be in equilibrium, as the

enantioselectivity is the same over the course of the reaction. If they were not
equilibrating, the enantioselectivity should be higher at lower conversions.
This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl

lithium complexes are equilibrating during the course of a reaction with an
electrophile.
Beak, Acc. Chem. Res, 1996, 552
[L2Rh]+
MeO2C
NHAc
MeO2C
NHAc
Rh
S,S
NHAc
The asymmetric hydrogenation of prochiral olefins catalyzed by

Rhodium is an important catalytic process.
MeO2C
Chem 206
Mechanism of Asymmetric Hydrogenation
Ph
coordination
coordination
CO2Me
MeO2C
HN
NH
Ph
Ph
> 95% ee
Enantioselectivities are generally very high when the ligand is a chelating
diphosphine. (ee's are given for S,S-CHIRAPHOS)
When a chiral ligand is used, there are two diastereomeric complexes which
may be formed:
NH
Rh
Ph
Me
minor complex 1
Rh
Ph
H2
Me
hydrogen
addition
O
Me
slow
NHAc
MeO2C
hydrogen
addition
slower
CO2Me
NH
HN
Rh
Ph
O
H
Rh
Ph
Me
O
H
Me
(NMR, X-Ray)
H2
NHAc
S
Ph
Me
faster
migration
+S
P
MeO2C
Rh
Ph
major complex
fast
major
MeO2C
P
P
minor
Ph
HN
P
P
Rh
CO2Me
MeO2C
Rh
P
Ph
CH2Ph
CO2Me
R
PhH2C
MeO2C
S
H
Rh
P
S
NH
migration
+S
observed product
HN
Me
Me
Observations:
Complex 2 is the only diasteromer observed for the catalyst-substrate complex
(1HNMR, X-Ray crystallography) in the absence of hydrogen
reductive
elimination
-L2RhS2
reductive
elimination
-L2RhS2
The enantioselectivity is strongly dependant on the pressure of H2, and

degrades rapidly at higher hydrogen pressures
The observed enantiomer is exclusively derived from the minor complex 2
These observations may be explained using the Curtin - Hammett Principle
MeO2C
NHAc
MeO2C
NHAc
Ph
Ph
> 95% ee
Halpern, Science, 217, 1982, 401
The Sharpless Epoxidation
! The literature precedent: Sheng, Zajecek, J. Org. Chem. 1970, 35, 1839
OR
RO
O
V
Chem 206
Sharpless Epoxidation (V+5)
D. A. Evans
O+
O
!
RDS
RO
HO
O
!
TBHP
OR
RO
O
O
!
Catalyst
ROH
ROOH
HO
O
!
OH
O
!
HO
OH
OH
VO(acac)2
Mo(CO)6
O
"
4:1
1:1
! Next step: Sharpless, Michaelson JACS 1973, 95, 6136
OR
RO
O
V
O
"
80 oC
OH
OR
OH
Me
VO(acac)2
TBHP
Me
O
"
Me
80 C
Me
Me
Regioselection 20:1
Me
Aldrichimica Acta, 12, 63 (1979)

OH
OH
Mo(CO)6
Stereoselection 98:2
(90 % yield)
TBHP
OC2C3C4 = 41
The Sharpless estimate: ~50
80 C
O
"
Relative Rates (Diastereoselectivities) for the Epoxidation of

Cyclohexene Derivatives JACS 1973, 95, 6136
t-BuOH
t-BuOOH
Substrate
HO
HO
2
1
OR
tBu
3
RO
4
O
V
O
O
O-OtBu
V
O
krela,b (diastereoselectivityc )
peracid
Mo(CO)6
VO(acac)2
1.00
1.00
1.00
0.55 (92 : 8)
4.5 (98 : 2)
>200 (98 : 2)
OH
OAc
0.046 (37 : 63) 0.07 (40 : 60)
--
tBu
Chem 3D Transition State
OH
slow
RO
V
O
O
0.42 (60 : 40)
11.0 (98 : 2)
10.0 (98 : 2)
a,b The relative rate data apply only to a given column.
Values in parenthesis refer to the ratio of syn:anti epoxide.
Epoxidation of Acyclic Alcohols
D. A. Evans
Chem 206
! Allylic Alcohols:
OH
Me
OH
Me
Me
OH
Reagent
Me
Me
O
"
"
O
Reagent
~ 120
40-50
m-CPBA
t-BuOOH / VO(acac)2
t-BuOOH / Mo(CO)6
CH
Me
OH
H
C
Me
Me
TSminor
t-BuOOH
R2
Ratio
64 : 36
29 : 71
62 : 38
64 : 36
VO(acac)2
R1
!
O
OH
R2
Me
H
SiMe3
R2
Yield
Ratio
H
C5H11
Bu
84 %
70 %
99 : 1
99 : 1
Me
Me
Me
!
O
VO(acac)2
60 %
EtO
OEt
O
Me
OH
OH
t-BuOOH
HO
OH
Me
Me
Me
OH
Reagent
Me
O
!
only isomer
Me
OEt
Me
!
O
VO(acac)2
60 %
EtO
OEt
Me
Me
Me
threo
O
!
OH
Me
Me
erythro
Reagent
m-CPBA
t-BuOOH / VO(acac)2
t-BuOOH / Mo(CO)6
Ratio
95 : 5
86 : 14
95 : 5
100 : 0
only isomer
Depezay, Tetrahedron Lett. 1978, 19, 2869.
Me
O
!
Me
VO(acac)2
60 % HO
OH
HO
t-BuOOH
OH
Boeckman, JACS 1977, 99, 2805.
K. B. Sharpless & Coworkers

R2
R1
Me
H TSminor
H
OEt
EtO
K. Oshima & Coworkers

Tetrahedron Lett. 1980, 21, 1657, 4843.
O
!
OH
O
EtO
Me
R1
SiMe3
OH
Me
Me
Me
Me
O
!
t BuOOH
HO
Me
Me
Reagent
m-CPBA
t-BuOOH / VO(acac)2
t-BuOOH / Mo(CO)6
Oshima, Tetrahedron Lett. 1982, 23, 3387.
OH
OH
SiMe3
OH
Me
O
!
OH
! V(+) Transition States: ! ~ 45

H
95 : 5
71 : 29
84 : 16
R1
Me
Ratio
Me
TSmajor
Me
erythro
! Estimate
TSmajor
Me
Me
threo
! RCO3H Transition States: ! ~ 120
OH
Reagent
OH
Me
NHCONHPh
Ph
m-CPBA
CH2Cl2, 0 C
75 %
Roush, J. Org. Chem. 1987, 52, 5127.
Me
NHCONHPh
Ph
O
!
Me
NHCONHPh
Ph
O
!
Chem 206
D. A. Evans
Anti diastereomer
Homoallylic Alcohols (Mihelich, JACS 1981, 103, 7690)
OH
t-BuOOH
OH
Me
O
!
+
OH
VO(acac)2
90 %
Me
O
!
Me
Me
Me
R1
Me
Me
Diastereoselection > 400 : 1
Control Elements
A(1,3) Strain
Directed Rxn
H
O
H
Me
HV
L'
O R
O
!
O H
!
R1
O
!
t-BuOOH
Me
Me
VO(acac)2
Et
Me
Et
Diastereoselection 12 : 1
Control Elements
Directed Rxn
Me
OH
H
O
L'
O R
HV
O
! H
OH
Ratio
C6H13
Me
Me
92 %
97 %
104 : 1
> 400 : 1
i-Pr
O
!
Me
Et
Et
R1
VO(acac)2
R2
Me
R1
Me
R1
R2
Yield
Ratio
C6H13
Me
Me
Me
73 %
70 %
70 : 1
85 : 1
81 %
16 :1
Me
C5H11
OH
t-BuOOH
C5H11
OH
O
!
R2
!O
Me
Me
OH
t-BuOOH
Me
Et
Me
Yield
VO(acac)2
OH
O
!
R1
R2
O
!
R2
OH
R2
Me
R1
OH
Me
Me
OH
R1
Syn diastereomer
HO
Me
R2
VO(acac)2
OH
O
!
t-BuOOH
R2
OH
OH
O
!
!O
Me
Me
Me
C5H11
Me
H
R2
O
R1
H
HV
L'
O R
! H
O
Me
Anti diastereomer
Anti should be more

diastereoselective
than syn
Product
Substrate
R2 H
O
R1
HV
L'
O R
O H
!
Me
OH
OH
2:1
!O
4.6 : 1
Me
Me
Me
Me
OH
Hex
!O
OH
OH
Syn diastereomer
Selectivity
Me
Me
OH
R
R = (CH2)7CO2Me
C5H11
E. D. Mihelich & Coworkers

J. Am. Chem. Soc. 1981, 103, 7690.
Epoxidation of Homoallylic Alcohols with TBHP, VO(acac)2
Prediction
OH
Hex
!O
1.4 : 1
D. A. Evans
Epoxidation & Cyclization of Bishomoallylic Alcohols
Bishomoallylic Alcohols (Kishi, Tet. Lett. 1978, 19, 2741)

R
OH
Me
t-BuOOH, VO(acac)2
CHMe2
C6H6, RT
Et
Et
Me
CHMe2
iPr
OH
VO(acac)2
OH
O
!
Chem 206
Me
iPr
OH
Et
Me
CO2H
O
!
OH
O R
Me
Et
Me
C6H6, RT
Me
CHMe2
Et
Me
Me
Et
Et
Et
OH
!
OH
Me
Ar = p-MeOPh
Ar
TBHP
AcOH
OH
Et
VO(acac)2
Et
B
Me
Me
Et
Ar
OH
O
!
t-BuOOH, VO(acac)2
CHMe2
HO
Me
OH
Me
Me
O
!
Me
OH
Et
iPr
Me
The Kishi Lasalocid Synthesis (JACS 1978, 100, 2933)

Me
AcOH
O
!
Et
H
Et
Et
Diastereoselection 8:1
OH
!
Et
Me
Me
H
Evans X-206 Synthesis JACS 1988, 110, 2506.
Et
Me
2nd stereocenter
is reinforcing
Me
Me
H
O
R
O
!
OH
O R
Me
Me
Me
O
!
Et
OH
Me
O
Me
OH
Me
Me
OH
Me
H
E
O
O
F
Me OH Me
O
D
OH
OH
Me
Et
OH
Me
t-BuOOH, VO(acac)2
CHMe2
Et
C6H6, RT
Me
OH
O
!
Me
Me
CHMe2
Et
Me
Me
R
H
O
Ph
OH
N
O
Et
OBn
Me
VO(acac)2
TBHP
C6H6, RT
O
!
Et
OBn
Me
HOAc
O
Me
Et
Me
O
!
O R
OH
XN
Et
Me
OH
OH
O
!
(89 %)
D
O
XN
OBn
Et
Me
OH
!
A New Enantioselective Epoxidation Reaction

H. Yamamoto et.al, Angew. Chem. Int. Ed. 2005, 44, 4389-4391
Diastereoselective Hydrogenation: Introduction
D. A. Evans
The Hydrogenation Reaction

Review article:
J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (handout)
! General Mechanism
M(0) +
R
C
H
C R
H
R C
H
Polar functional groups may play a role in controlling the diastereoselectivity

of the hydrogenation process;
however, the control elements were not well-defined.
CHMe2
M
C
R
C
H
R
H
C R
H
H
H
R
H
H
C
R
H
M
R
H
R
C
H
R
H
H2, Pd-C
only isomer
CH3
CHMe2
M(0) +
Chem 206
however
CH3
CHMe2
C R
H
CHMe2
OH
Historically, primary stereochemical control designed around analysis of

steric environment in vicinity of C=C.
OH
H2, Pd-C
trans:cis = 55:45
H
CH3
H
CH3
However, the influence of polar effects was documented

J. E. McMurry & Co-workers, Tetrahedron Lett.. 3731 (1970)
O
CO2Et
H2 Pd-C
CO2Et
10% Pd-C
EtOH
H
OMe
Pd(II)
CH2OH
H2 Pd-C
H
H
5% Pd-Al2O3
H
OMe
H2
OMe
OH
Thompson, J.Org. Chem. 36, 2577 (1971)
trans : cis
5 : 95
sole product
HO
EtOH
Steric Control
OH
CH2OH
HO
trans : cis
85 : 15
LiAlH4
H2
OMe
Pd(0)
HO
Directed ?
12 : 1
Y. Kishi & Co-workers, J. Am. Chem. Soc. 102, 7156 (1980)
Diastereoselective Hydrogenation: Introduction-2
D. A. Evans
The first rational attempt to identify those FGs which will direct the reaction
Chem 206
Cationic Hydrogenation Catalysts
H
O
CH3O
H2, 5% Pd-C
O
CH3O
10
95 : 5
93 : 7
75 : 25
55 : 45
18 : 82
15 : 85
14 : 86
10 : 90
The first rational attempt to associate catalyst with substrate:

CH2OH
MeO
Py
(CH2)n
Schrock & Osborne,
J. Am. Chem. Soc. 91, 2816 (1969)
S
H2
Rh
H2
16-e
Rh
CH2=CH2
Rh
PPh2
(+S)
CH3CH3
H2
18-e
Rxn Catalytic in Rh (4 mol%)

H2C
S
Rh PPh2
Ph2P
S
PPh2
Oxidative
Addition
(S)
Thompson & Coworkers, J. Am. Chem. Soc. 97, 6232 (1974)
PPh2
Ph2P
Ph2P
Reductive
Elimination
CH2ORh(PPh3)3
MeO
Rh
H
Ph2P
S = solvent
S = solvent
MeO
cis : trans
>98 : 2
Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts.
S
H
S
BF
PPh2
Rh(+I): d8
PF6
PCy3
R. Crabtree
J. Organomet. Chem. 168, 183 (1979)
Ph2P
(Ph3P)3RhCl
H2 100 psi
50 C, C6H6
Ir
(CH2)n
H. Thompson & Co-workers, J. Am. Chem. Soc. 95, 838 (1973)
CH2OK
PPh2
cis : trans
CH2OH
CHO
CN
COONa
COOH
COOMe
COMe
CONH2
BF
4
Rh
Ph2P
Rh
Ph2P
S
PPh2
Diastereoaselective Hydrogenation: Cationic Catalysts
D. A. Evans
Chem 206
D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984)
Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts.
OH
2H2
Rh
+2 S
Ph2P
BF
4
Ph2P + PPh2
PPh2
18-e
16-e_
S = solvent
Rh
PPh2
HA
Rh
HB
H
C
H
H
H2
R2
OH
CH2
OH
Ir(pyr)PCy3
R2
Which hydrogen
migrates ??
P
P
OH
OH
CH3
Rh
CH3
H2 Pressure
trans:cis (Yield)
17.5
15 psi H2
200 : 1 (89%)
3.5
375 psi H2
300 : 1 (95%)
20.0
15 psi H2
50 : 1 (82%)
2.5
15 psi H2
150 : 1 (85%)
Rh +
H2
OH
CH3
OH
CH3
19 : 1
Rh(DIPHOS-4)+ H2 1000 psi CH2Cl2
CH2OH
Rh +
H2
CH3
65 : 1
CH2OH
CH3
H
R2
Me
Me
P
P
Me
P
OH
C
HB
R2
H
HA
HA
Rh
Me
CO2H
Me
Excessive Steric Hindrance

Me
H
Me
A potential stereoelectronic effect
HA
Rh
HB
H
C
H
H
CH3
Rh
P
Mol% Catalyst
R2
Catalyst
Rh(DIPHOS-4)+
CH2Cl2
CH3
H
Ph2P
P
P
H2
H2
BF
4
Rh
OH
+ H
Me
Retigeranic Acid
Me
OH
That H atom lying parallel to the pi-system (HA) should

migrate preferentiallyif the dihydride is an intermediate.
OH
Me
Me
Me
Rh +
R2
OH
H
Me
Me
Me
H2
Me
H
Me
OH
75 : 1 (95%)
Rh(DIPHOS-4)+ H2 800 psi THF

THF is important to success of rxn to buffer the Lewis acidity of the catalyst which
causes elimination of ROH under normal conditions
Diastereoselective Hydrogenation: Cyclic Substrates
D. A. Evans
Polar functional groups other than OH may also

direct the process
Rh(DIPHOS-4)+
H2
H2C
CH3
H2
CO2Me
Ir(pyr)Pcy3+
H2
diastereoselection
89:11
CH3
Ir(pyr)Pcy3+
diastereoselection
91 : 9
CO2Me
CH3
O
X
CO2Me
CO2Me
Chem 206
Me
Me
CH3
X
CH3
Ir(pyr)Pcy3+
CH3
X
OMe
55:45
NC4H8
99:1
NC4H8
Me
Me
OCH3
J.M. Brown and S.A. Hall, J. Organomet. Chem., 1985, 285, 333.
O
Ir(pyr)Pcy3+
H
CH2OMe
O
CH3
H2
N
CH3
Me
N
Ir(pyr)Pcy3+
H2
>99:1
diastereoselection
>99:1
H2
Me
99:1
A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.
Ir(pyr)Pcy3+
Diastereoselection
OMe
X
CH3
H2
Diastereoselection
N
CH3
CH3
O
N
H
N
H
diastereoselection
>99:1
OCH3
15 psi H2
Ir(pyr)Pcy3+
diastereoselection
>99:1
CH3
R.H. Crabtree and M.W. Davis, J. Org. Chem., 1986, 51, 2655.
O
CONC4H8
CH2OMe
15 psi H2
Ir(pyr)Pcy3+
CONC4H8
diastereoselection
>99:1
O
CH3
diastereoselection
>99:1
CH3
CH3
Diastereoselective Hydrogenation: Acyclic Substrates
D. A. Evans
Acyclic Allylic Alcohols

P
+
Rh
favored
H2
H
R1
R2
OH
+
OH
Rh
OH
+
Rh
R1
P
H
CH2
R2
CH2R2
anti
R2
R1
CH2
+
Rh
R2
H
CH3
R1
H
C
CH2R2
disfavored
Rh
H2
R2
R1
CH2R2
Me
anti > 93 : 7
R1
OH
OH
R1
R1
+
Rh
OH
Rh
Me
OH
R2
Chem 206
Rh
OH
R1
OH
CH3
H2
R2
Me
syn > 91 : 9
OH
H2
+
OH
R2
Me
Me
syn
OH
R1
CH2
OH
Ph
H2
Rh(DIPHOS-4)+
COXn
Me
R1
Me
Me
anti
low pressure
P
P
+
Rh
favored
Rh
R2
R2
R1
OH
OH
+
OH
H2
OH
R2
CH3
R1
Me
Ph
N
Me
syn
Me
Hydroxy-Olefin
+
Rh
disfavored
Me
Me
Anti : Syn Ratio
Me
COXn
R1
OH
Me
H2
Rh(DIPHOS-4)+
R2
R1
H
C
H
P
Rh
+
OH
Me
OH
H2
R2
D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984)
D
R1
Me
anti
T
15 psi H2
640 psi H2
R = CH3
25 : 75 (23%)
93 : 7
R = (CH3)2CH
52 : 48 (35%)
94 : 6
R = Ph
71 : 29 (-)
93 : 7
R = CH3
13 : 87 (6%)
9 : 91
R = (CH3)2CH
12 : 88 (8%)
8 : 92
R = Ph
21 : 79 (-)
6 : 94
syn
Diastereoselective Hydrogenation: Acyclic Substrates
D. A. Evans
Homoallylic Alcohols
The Premonensin Synthesis
Evans, Morrissey Tetrahedron Lett. 26 6005 (1985)

OH
+
Rh
C
Me
P Rh
favored
OH
O+
H
Me
H
H2
HO
Me
Me
HO
Me
Me
OH
CH2
Chem 206
OH Me
C
Me
syn
Me
Et
Me
Me
Me
R
Me
Me
disfavored
+
Rh
Me
P H
O+
Rh
CH2
C
OH
H2
C
Me
Me
Me
Me
HO
H2
Me
Me
Me
A
A
85 : 15
Rh()(BINAP) +
65 : 35
Rh(+)(BINAP) +
98 : 2 (90%)
Me
Me
syn
Me
OH
OH
Me
HO
Me
Rh(DIPHOS-4) +
The Ionomycin Synthesis
Me
HO
OTBS
Catalyst (H2 Pressure)

Rh(DIPHOS-4)+ (1000 psi)
Ir(pyr)PCy3+ (15 psi, 2.5 mol%)
OTBS
Me
Ratio
Evans, DiMare, JACS, 1986, 108, 2476)
OTBS
Olefin
HO
Me
anti
HO
Me
Me
OTBS
EtO2C
Rh +
A(1,3) destabilization
HO
Catalyst
Me
Me
EtO2C
Me
HOOC
Me
Me
Me
O
Me
anti
Me
Me
syn : anti
H2
CH3O2C
95 : 5
Me
Me
OH
Me
Rh(DIPHOS-4)+
Me
!
CH3O2C
OH
73 : 27
9 : 91
OH
Me
Me
Rh(DIPHOS-4)+ (1000 psi)
Me H
Me
Me
Diastereoselection: 94 : 6 (93%)
with Dow, Shih, Zahler, Takacs, JACS 1990, 112, 5290
}
D. A. Evans, T. B. Dunn
Pericyclic Reactions: Part1
Chem 206
! Other Reading Material:

! Woodward-Hoffmann Theory
R. B. Woodward and R. Hoffmann, The Conservation of Orbital
Symmetry, Verlag Chemie, Weinheim, 1970.
Chemistry 206
! Frontier Molecular Orbital Theory

I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
John-Wiley and Sons, New York, 1976.
Lecture Number 11
! Dewar-Zimmerman Theory
T. H. Lowry and K. S. Richardson, Mechanism and Theory in
Organic Chemistry, 3rd Ed., Harper & Row, New York, 1987.
Pericyclic Reactions1
! General Reference
R. E. Lehr and A. P. Marchand, Orbital Symmetry: A Problem
Solving Approach, Academic Press, New York, 1972.
! Introduction to Pericyclic Reactions
! Electrocyclic Reactions
! Sigmatropic Reactions
Predict the stereochemical outcome of this reaction.
! Cycloaddition Reactions
Ph O
Ph
"

Concerted Pericyclic Reactions
Fleming: Chapter 4
Thermal Pericyclic Reactions
Ph
"
heat
Huisgen, TL, 1964, 3381.
Ph
Suggest a mechanism for the following reaction.

CO2Me
Wednesday,
October 12, 2005
heat
MeO2C
CO2Me
Bloomfield, TL, 1969, 3719.
CO2Me
H
D. A. Evans, B. Breit, T. B. Dunn
Pericyclic Reactions: Introduction
Chem 206
Pericyclic Reactions - Introduction/Definitions

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.
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.
Pericyclic Reactions: Introduction
Some factors to consider in our analysis:
Chem 206
2) Dewar-Zimmerman: Aromatic Transition States
The number of electrons involved has a profound influence on reactivity:
The easiest to apply for all reaction types, but it is not as easy to
understand why it it valid
Aromatic or antiaromatic transition states
heat
heat
rarely
observed
often
observed
4 electrons
6 electrons
3) Woodward-Hoffmann: Conservation of Orbital Symmetry

First theory to explain and predict the outcome of many reactions
Correlation diagrams
The Five Major Classes of Pericyclic Reactions
Pericyclic reactions are stereospecific:

A
A
(1) ELECTROCYCLIC RING CLOSURE/RING OPENING:
A
A
heat
heat
An electrocyclic ring closure is the creation of a new

sigma bond at the expense of the terminal p orbitals
of a conjugated pi system. There is a
corresponding reorganization of the conjugated pi
system. We classify the reaction according to the
number of electrons involved.
Examples:
Reactions behave differently depending on the conditions used

(i.e. thermal versus photochemical conditions):
A
A
heat
h!
A
The Theories:
A 4 e- electrocyclic reaction
Three theories are commonly used to explain and predict pericyclic

reactions. We will only concern ourselves with two of these theories.
1) Fukui: Frontier Molecular Orbital Interactions
Much easier to use than the original orbital symmetry arguments
HOMO/LUMO interactions
! or h"
Cyclobutene
A 6 e- electrocyclic reaction
! or h"
Butadiene
1,3,5-Hexatriene
1,3-Cyclohexadiene
Pericyclic Reactions: Major Classes
Chem 206
(2) CYCLOADDITION REACTIONS/CYCLOREVERSION REACTIONS:

A cycloaddition reaction is the union of two smaller, independent pi systems.
Sigma bonds are created at the expense of pi bonds.
Cycloaddition reactions are referred to as [m + n] additions when a system of
m conjugated atoms combines with a system of n conjugated atoms.
A cycloreversion is simply the reverse of a cycloaddition.
Examples:
[2+2]
h!
[4+2]
+
"
A 2+2 cycloaddition.
The Paterno-Bchi
reaction.
A 4+2 cycloaddition.
The Diels-Alder reaction.
Chem 206
(3) CHELETROPIC REACTIONS:

Cheletropic reactions are a special group of cycloaddition/cycloreversion
reactions.
Two bonds are formed or broken at a single atom.
The nomenclature for cheletropic reactions is the same as for cycloadditions.
Examples:
O
+
[4+1]
S
O
+ C O
CR2
[4+1]
[2+1]
R
R
Chem 206
(4) SIGMATROPIC REARRANGEMENTS:

A sigmatropic rearrangement is the migration of a sigma bond from one position in a
conjugated system to another position in the system, accompanied by reorganization of
the connecting pi bonds.
The number of pi and sigma bonds remains constant.
The rearrangement is an [m,n] shift when the sigma bond migrates across m atoms
of one system and n atoms of the second system.
Examples:
2
2
[1,3]-shift
3'
1'
2'
[1,5]-shift
R2
R1 H
2
3
[3,3]-shift
R1
R2
2
3
X
R
3'
1'
2'
X=CR2, Cope rearrangement

X=O, Claisen rearrangement
Chem 206
(5) GROUP TRANSFER REACTIONS:

In a group transfer reaction one or more groups get transferred to a second
reaction partner.
Examples:
R
Hydrogen
Transfer:
H
+
+
H
N
N
H
R
H
+
H
N2
R'
R'
Ene Reaction:
+
H
Electrocyclic Reactions
Chem 206
Butadiene to cyclobutene: A 4-electron (4q) system
ELECTROCYCLIC RING CLOSURE/RING OPENING:

The Stereochemical issues:
Ring closure can occur in two distinct ways. This has consequences
with regard to:
Me
Me
Me
conrotation
heat
! The orbital lobes that interact

! The disposition of substituents on the termini
Me
conrotation
Conrotatory Closure: The termini rotate in the same direction
Me
Me
Me
heat
Me
Hextriene to cyclohexadiene: A 6-electron (4q+2) system

B
B
A
B
A
disrotation
H H
Me
Disrotatory Closure: The termini rotate in opposite directions
Me
Me
Me
A
A
disrotation
!
Me
Empirical Observations:
It was noted that butadienes undergo conrotatory closure
under thermal conditions, while hexatrienes undergo
disrotatory closure under thermal conditions. The
microscopic reverse reactions also occur with the same
rotational sense (i.e. cyclobutenes open in a conrotatory
sense when heated, and cyclohexadienes open in a
disrotatory sense when heated.)
Me
Me
Me
It was also noted that changing the "reagent" from heat to

light reversed this reactivity pattern. Under photochemical
conditions 4 electron systems undergo disrotatory motion,
while 6 electron systems undergo conrotatory motion.
Me
disrotation
h!
Me
Me
Me
controtation
h!
Me
Me
Me
Me
Conjugated pi systems
D. A. Evans, T. B. Dunn
Chem 206
6 p-orbitals
antibonding
4 p-orbitals
3 p-orbitals
5 p-orbitals
!4
2 p-orbitals
!3
"#
nonbonding
!3
!2
nonbonding
!2
"
!1
!1
bonding
There are no nodal planes in the most stable bonding MO. With each higher MO, one additional nodal plane is added.
The more nodes, the higher the orbital energy.
Electrocyclic Reactions: FMO Analysis
FMO Treatment of Electrocyclic reactions.

Examine the interactions that occur in the HOMO
as the reaction proceeds.
If the overlap is constructive (i.e. same phase) then
the reaction is "allowed."
If the overlap is destructive (different phases) then
the reaction is "forbidden."
Photochemical Activation:
When light is used to initiate an electrocyclic rxn, an
electron is excited from 2 to 3. Treating 3 as
the HOMO now shows that disrotatory closure is
allowed and conrotatory closure is forbidden.
!4
!3
!2
Me
Me
Me
Me
Photon
absorption
Me
!3 (HOMO)
Disrotatory Closure: (Allowed and observed)

H
Me
Me
!2 (diene HOMO)
!1
Conrotatory Closure: (Allowed and observed)
!2 (HOMO)
Me
!4
!3
Me !2
!1
h"
Thermal Activation:
Me
Chem 206
Me
Me
Me
Me
Me
Constructive
overlap
!3 (new HOMO)
Constructive
overlap
Me
Conrotatory Closure: (Forbidden and not observed)

Disrotatory Closure: (Forbidden and not observed)
H
Me
Me
!2 (diene HOMO)
Me
Me
Me
H
Me
Destructive
overlap
A similar analysis for the hexatriene system proves

that under thermal conditions, disrotation is allowed
and conrotation is forbidden.
Me
Me
!3 (new HOMO)
Me
Me
H
Me
H
Me
Destructive
overlap
We have so far proven which ring closures are allowed and which are
forbidden. Do we now have to go back and examine all the ring
openings?
NO!
The principle of microscopic reversiblity says that if the reaction is

allowed in one direction, it must be allowed in the other direction.
Electrocyclic Reactions: Dewar-Zimmerman
The Dewar-Zimmerman analysis is based on identifying

transition states as aromatic or anti-aromatic. We will not go
into the theory behind why this treatment works, but it will give
the same predictions as FMO or Orbital Symmetry
treatments, and is fundamentally equivalent to them.
Using the Dewar-Zimmerman Model:
Chem 206
Connect
Orbitals
Disrotatory
Closure
Conrotatory
Closure
Choose a basis set of 2p atomic orbitals for all atoms

involved (1s for hydrogen atoms).
Assign phases to the orbitals. Any phases will suffice. It is
not important to identify this basis set with any molecular
orbital.
Connect the orbitals that interact in the starting compound,
before the reaction begins.
Allow the reaction to proceed according to the geometry
postulated. Connect those lobes that begin to interact that
were not interacting in the starting materials.
Zero Phase Inversions

!Hckel Topology
4 electrons in system
! Antiaromatic and
Forbidden
One Phase Inversion

!Mbius Topology
! Aromatic and
Allowed
Note that I can change the phase of an abitrary orbital and the
analysis is still valid!
Connect
Orbitals
Count the number of phase inversions that occur as the

electrons flow around the circuit. Note that a phase inversion
within an orbital is not counted.
Based on the phase inversions, identify topology of system.
Odd number of phase inversions: Mbius topology
Even number of phase inversions: Hckel topology
Assign the TS as aromatic or antiaromatic, based on number
of electrons present.
System
Hckel
Mbius
Aromatic
4q + 2
4q
Antiaromatic
4q
4q + 2
If TS is aromatic, then the rxn will be thermally allowed.

If TS is antiaromatic, then the rxn will be photochemically allowed.
Disrotatory
Closure
Two Phase Inversions

!Hckel Topology
! Antiaromatic and
Forbidden
Conrotatory
Closure
Three Phase Inversions

!Mbius Topology
! Aromatic and
Allowed
[1,3]-Sigmatropic Rearrangements: FMO Analysis

The migrating group can move across the conjugated pi system
in one of two ways. If the group migrates on the same side of
the system, it is said to migrate suprafacially with respect to
that system. If the group migrates from one side of the pi
system to the other, it is said to migrate antarafacially.
Suprafacial migration: The group moves across the same face.
A
B
A
[1,3] Sigmatropic Rearrangements (H migration)

Construct TS by considering an allyl anion and the proton
(or aradical pair):
H
X
Chem 206
A
B
Proton 1S (LUMO)
Antarafacial migration: The group moves from one face to the other.
bonding
B
A
A
A
B A
bonding
antibonding
!2 (allyl anion HOMO)

bonding
Sigmatropic Rearrangements: FMO Analysis

Imagine the two pieces fragmenting into a cation/anion
pair, (or radical pair) next examine the HOMO/LUMO
interaction.
If the overlap is constructive at both termini then the reaction is
allowed. If the overlap is destructive at either terminus then
the reaction is forbidden.
If the migrating atom is carbon, then we can also entertain
the possiblity of the alkyl group migrating with inversion of
configuration (antarafacial on the single atom).
If the migrating atom is hydrogen, then it cannot migrate with
inversion.
Suprafacial Geometry
Antarafacial Geometry
The analysis works if you consider the other ionic reaction,

or consider a radical reaction. In each case it is the same
pair of orbitals interacting.
Suprafacial migration is forbidden and the bridging distance
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?
[1,3]-Sigmatropic Rearrangements
[1,3] Sigmatropic Rearrangements (C migration)

CH3
CH3
X
Sigmatropic Rearrangements: Dewar-Zimmerman
CH3
X
Chem 206
DZ also predicts [1,3] suprafacial migration to be

forbidden.
The basis set of s and p orbitals with arbitrary phase:
Construct TS by considering an allyl anion and the methyl

cation:
Retention at carbon
Inversion at carbon
C
H H
antibonding
bonding
bonding
2p on Carbon
H
C H
H
H H
!2 (allyl anion HOMO)
Suprafacial on allyl fragment

Hckel Topology
Four Electrons
Forbidden thermally
H H
bonding
Orbital interactions in
the parent system
Completing the circuit

across the bottom face
The [1,5] shift of a hydrogen atom across a diene.
The analysis works if you consider the other ionic reaction,

or consider a radical reaction. In each case it is the same
pair of orbitals interacting.
H
Under photochemical conditions, the [1,3] rearrangement is

allowed suprafacially with retention of stereochemistry.
Stereochemical constraints on the migration of carbon
with inversion of configuration is highly disfavored on the
basis of strain. Such rearrangements are rare and usually
only occur in highly strained systems.
Using a similar analysis, one can prove that [1,5] hydrogen
and alkyl shifts should be allowed when suprafacial on the pi
component and proceeding with retention. Refer to Fleming
for more applications of FMO theory to [1,n] sigmatropic
shifts.
H
Hckel Topology
Six Electrons
Allowed thermally
Orbital interactions in
the parent system
Completing the circuit

across the bottom face
[3,3]-Sigmatropic Rearrangements
[3,3] Rearrangements:
! The Toggle Algorithm:
A thermally allowed reaction is possible in either of two

geometries, the "chair" or the "boat" geometry. Depicted
below is the "chair" geometry. You should be able to work out
the details of the "boat" geometry yourself.
The toggle algorithm is a simple way to take one reaction of each

class that you remember is allowed (or forbidden) and derive if the
reaction is allowed or forbidden under new conditions.
! How does it work?

All of the various parameters of the pericyclic reaction are the
input variables, the "switches."
The output is either "allowed" or "forbidden."
Write out all the relevant parameters of a reaction together with
the known result.
Each time you change a parameter by one incremental value
("toggle a switch"), the output will switch.
This is the prediction of the reaction under the new parameters.
X
Z
X & Z = C, O, N etc
The FMO Analysis:

Bring two Allyl radicals together to access for a possible bonding
interaction between termini.
The nonbonding
allyl MO
Chem 206
bonding
! So it's nothing really new, is it?

No, its just a convenient way to rederive predictions without
memorizing a table of selection rules.
An Example:
Take the [1,3] sigmatropic rearrangement of an alkyl group. We
know this is forbidden under thermal conditions in a supra-supra
manner, and so we make it the first entry in the table.
Rearrangement Conditions Component 1 Component 2
!2
bonding
The Dewar-Zimmerman Analysis:

Hckel Topology
Six Electrons
Allowed Thermally
Output
[1,3]
Heat
Suprafacial
Suprafacial
Forbidden
[1,3]
Heat
Antarafacial
Suprafacial
Allowed
[1,3]
Light
Antarafacial
Suprafacial
Forbidden
[1,5]
Heat
Suprafacial
Suprafacial
Each incremental change in the "input" registers changes the

"output" register by one. Multiple changes simply toggle the output
back and forth. What is the prediction in the last line?
Cycloaddition Reactions
Chem 206
The [4+2] Cycloaddition: Dewar-Zimmerman

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.
Suprafacial
attack
The most well known cycloaddition is the Diels-Alder reaction between

a four pi component (the diene) and a two pi component (the
dienophile). An exhaustive examination of this reaction is forthcoming,
so we will limit ourselves to a simple examination.
Antarafacial
attack
Hckel Topology
Six Electrons
Allowed thermally
The [2+2] Cycloaddition: FMO Analysis

For the [2+2] cycloaddition two different geometries have to be
considered.
Suprafacial/Suprafacial
HOMO
bonding
Antarafacial/Suprafacial
bonding
HOMO
! There are three fundamentally equivalent methods of analyzing

pericyclic reactions: Two are much simpler than the third.
! Fukui Frontier Molecular Orbital Theory
! Dewar-Zimmerman Hckel-Mbius Aromatic Transition States
! Woodward-Hoffmann Correlation Diagrams
antibonding
LUMO
bonding
LUMO
Forbidden
Summary:
Allowed
The simplest approach (Supra/Supra) is forbidden under thermal

activation. The less obvious approach (Antara/Supra) is allowed
thermally but geometrically rather congested. It is believed to occur in
some very specific cases (e.g. ketenes) where the steric congestion is
reduced.
! Some methods are easier to use than others, but all are equally
correct and no one is superior to another. Conclusions drawn from
the correct application of one theory will not be contradicted by
another theory.
! The principle of microscopic reversibility allows us to look at a
reaction from either the forward direction or the reverse direction.
! There is a general trend that reactions will behave fundamentally
different under thermal conditions and photochemical conditions.
D. A. Evans
Chem 206
! Predict stereochemical outcome

Me
OR
OR
Me
Chemistry 206
Me
OH
O
Me
OH
Me
Me
Hg(OAc)2, CH2Cl2
-78 oC to -20 oC
Lecture Number 10
99%
Olefin Bromination
Olefin Oxymercuration
Halolactonization
Simmons-Smith Reaction
Me
Me
Me

D. A. Evans
Monday,
October 10, 2005
Me
Hg(OAc)2, CH2Cl2
-78 oC to -20 oC
XHg
BnO
"
O
Me
Me H
O
O
85%, dr = 93 : 7
Bromoniun Ions or !-Bromocarbocations in Olefin Bromination. A

Kinetic Approach to Product Selectivities
M-F. Ruasse, Accts. Chem. Res. 1990, 23, 87 (pdf)
HgX Me
OH
OH
Me
Investigation of the early Steps in Electrophilic Bromination through the

Study of the Reaction of Sterically Encumbered Olefins
R. S. Brown, Accts. Chem. Res. 1997, 30, 131 (handout)
Me
16
Me
O
O
99%, single diastereomer
HO
Me
Me
OR
O "
BnO
OR
Me

!
!
!
!
X-206 Synthesis
(with S. Bender, JACS 1988, 110, 2506)
Me
Me
OH
Me
Me
Me
Ionomycin Synthesis
(with Dow & Shih, JACS 1990, 112, 5290)
Olefin Bromination-1
D. A. Evans
R
Introduction
R
R
Br
Br2
Chem 206
! Bromonium ion origin of the anti (trans) selectivity first suggested by

Roberts, JACS 1937, 59, 947
Br
R
! Reaction is first order in alkene

At low concentrations of Br2, rxn is also first order in Br2
Br
Br2
Br
At higher concentrations of Br2 in nonpolar solvents rxn is 2nd order in Br2.

! Substituent Effects on Bromination Rates
CH3CH=CH2
61
n-PrCH=CH2
70
i-PrCH=CH2
57
t-BuCH=CH2
27
(CH3)2C=CH2
5470
cis-CH3CH=CHCH3
2620
Br
2 eq Br2
-2 eq Br2
1700
trans-CH3CH=CHCH3
130,000
(CH3)2C=CHCH3
Br-3
Br-2
1,800,000
(CH3)2C=C(CH3)2
Br-4
! Stereochemical outcome versus structure (Br2 in HOAc @ 25)

Alkene
H
% anti addition
Alkene
H
X-ray structure
Br-1
% anti addition
Me
100%
2.194
2.116
83%
Me
Me
Ph
Me
Me
100%
63%
Me
Ph
Me
Me
Me
Ph
Me
Ph
73%
Br
R
Br3
CH2=CH2
R
Br
! First X-ray Structure of a bromonuium ion: Brown, JACS 1985, 107, 4504
krel
Alkene
+
R
68%
1.497
Chem 206
! Calculated Geometries of Substituted Bromonium Ions

Ruasse, Chem Commun. 1990, 898
More recent calculations: Sigalas, Tetrahedron 2003, 59, 4749
Overall Reaction Mechanism

Second Order Kinetics
Br
Br
2.01
H
H
1.47
Br
2.70
1.88
1.51
2.05
Me
Me
Me
Me
1.51
Me
"-complex
Br2
Br2
Me
(!-complex)
Note; the CBr bond lengths in previous X-ray structure are 2.116 .
B
! Bromonium Ions undergo fast exchange with olefins
Brown, Accts. Chem. Res. 1997, 30, 131
Br2
Br
Br3
"-complex
Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480
AdC CAd
Br
Br
AdC CAd
Br3
R
Me3C
AdC CAd
106
M1
s-1
X = Br: exchange rate: 2 x

AdC CAd X = I : exchange rate: 8 x 106 M1 s-1
Br
PyrBr+ Br3
Me3C
Products
Br3
Third Order Kinetics
Unprecedented until 1991 (Bennet, JACS 1991, 113, 8532)
AdC CAd
Products
Br
Br.HOR
R = H, Me
exclusive
product
Br
Diaxial opening of bromonium ions may be viewed as an extension of the

Furst-Plattner Rule for epoxide ring opening (Lecture-3).
OMe
There is an intermediate in the halogen transfer (ab initio calcs):

PyrBr+ Br3
R
R
R
R
R
R
+ Br
complex
+ Br
R
R
R
R
R
R
R
R
R
R
TS
MeOH
H
Me3C
R
R
R
R
complex
H
H
Br
+ Br
Br
Me3C
Me3C
MeOH
Me3C
H
Me3C
Br
47%
53% Br
H
OMe
It appears that bromine attack from both olefin faces occurs wilth
near equal probability.
D. A. Evans
Representative Examples of Diastereoselective Bromination

Furst-Plattner Rule for epoxide ring opening. (Lecture-2)
Br3
MeOH
H
Me3C
Br
H
H
47%
Case B
PyrBr+
Me3C
MeOH
Me3C
H
Me
MeOH
Me3C
Minor Product
(7%)
OMe
H
H
Me
Me
H
H
Br
Br
Br
OMe
Me3C
H
R
Br
53%
Br3
House 2nd Ed, pg 424
Br
Me
HH
Br
H
Br2
Br
Me3C
Br
HOAc
Me3C
Me
OMe
Case A
PyrBr+
Chem 206
Me
H
H
Br
Major Product
(70%)
How to generate either epoxide from a conformationaly biased olefin

exclusive
product
Me
Me
RCO3H
Br
Epoxidation controlled by steric

effects imposed by cis-fused ring
H
O
Br !+
Me
Me3C
!+
How do we construct the other epoxide diastereomer??

H
Me3C
Me
Me
Br
H
anti-Reactive
syn-Unreactive
Me
Br2
H2O
Br
Br
H2O
!+Me
H
Me
Br
Me3C
Me3C
syn-Unreactive
HOMe
H2O
Br
H+
H
H
Me
not
observed
Me
OMe
From Case A, one assumes that both bromonium ions are formed; however, for the syn
isomer to react, ring opening must proceed against the polarization due to Methyl
substituent. Therefore it is reasonable that bromoniun ion exchange must be occuring.
Me
base
H
H
H
O
H
Me
Br
Br
H H
both bromohydrins afford same product
OH
OH
minor
major
Olefin Oxymercuration-1
D. A. Evans
Oxymercuration Pasto, JACS 1970, 92, 7480
The basic process:

H
XHgX
ROH
XHg
H
H
C
NaBH4
OR

Furst-Plattner Rule for epoxide ring opening. (Lecture-2)
H
C
OR
Kinetics: Halpern, JACS 1967, 89, 6427 Reduction: Pasto, JACS 199, 91, 719
Overview: B rown, JOC 1981, 46, 3810.
Me3C
OH
Hg(OAc)2
THF, H2O
Me3C
Me3C
H
R=H
41%
48%
R = Me
100%
Me
Hg(OAc)2
Me3C
H
H
PyrBr+ Br3
MeOH
H
Br
Me3C
MeOH
HgOAc
!+
!+Me
Me3C
HgX
H
anti-Reactive
syn-Unreactive
NaBH4
PyrBr+ Br3
RDS
Br !+
!+
Me
Me3C
Br
H
anti-Reactive
MeOH
not
observed
HgH
H
H
R Hg
Formate is an excellent source of hydride ion for

late transition and heavy main-group metals
O
OMe
H
H
Me
H
MeOH
Me3C
OMe
CO2
Me
Me3C
nonstereoselective radical
chain process
HCO2
exclusive
product
Br
Me3C
Me
Me3C
Br !+
OMe
Me
Reduction of the HgC bond

R HgX
53%
Case B
Me
H
Me3C
Br
H
syn-Unreactive
HgX
Br
Me3C
Me3C
exclusive
product
Br
Me
47%
OH
Me3C
Me3C
OH
THF, H2O
HgOAc
Me3C
HgOAc
OMe
Case A
Me3C
Oxy-Mercuration & bromination follow identical pathways (Pasto)

R
Chem 206
Me
Br
Me
fast
Me3C
From Case A, one assumes that both bromonium ions are formed;
however, for the syn isomer to react, ring opeing must proceed against
the polarization due to Methyl substituent.
Oxymercuration Examples
D. A. Evans
! Acyclic allylic alcohols:
Diastereoselective ring closures via oxymercuration

H
BnO
BnO
H
Hg(OTFA)2
OBn
O
BnO
BnO
NaBH4
OH
OBn
OH
OC6H11
!:" = 96 : 4
H
H
AcNH
R'
OR
OH
CO2Me
AcNH
Ph3SiH
H OBn
HO
Me
OR
X
OH
"one isomer"
O
NaBH4
R
-Et
-Et
R'OH
HOH
MeOH
Ratio
76 : 24
93 : 07
yield
65%
72%
-Ph
HOH
88 : 12
66%
-tBu
-tBu
HOH
98 : 02
70%
Giese, Tet. Lett. 1985, 26, 1197
HO
HO Me H
Hg
HO
Hg(OAc)2
RL
H
Hg(OAc)2
OR'
OR'
Sinay, Tet. Lett. 1984, 25, 3071
OBn
OH
H
H
OR
OH
HO
Hg(OAc)2
n-Bu
Hg
Me
OH
H
H
H N
BnO2C
H
Hg(OAc)2
NaBH4
Harding, JOC 1984, 49, 2838
Me
XHgCH2
N
BnO2C
H
CH2HgX
Me
H
N
BnO2C
H
Hg(OAc)2: short rxn times : 40 : 60
Me
syn:anti = 80 :20
O-acetate participation will turn over the stereochemical course of the rxn
OAc
HOH
NaBH4
Et
OAc
Hg(OAc)2
Et
OH
Me
OH
Hg(OTFA)2: longer rxn times : 2 : 98
Me
Et
erythro
OAc
erythro:threo = 77 : 23
Me
Me
Hg(OAc)2
With more electrophilic Hg(II) salt, more polar solvents, and

longer rxn times, the rxn may be rendered reversible.
OH
HgOAc
HOH
Chamberlin, Tetrahedron 1984, 40, 2297
H
Me
RL
Me
RL
HgOAc
OH
RL
OBn
! Kinetic vs Thermodynamic control:
RL
HOH
Isobe, Tet. Lett. 1985, 26, 5199
Me
HgOAc
CO2Me
H OBn
R'OH
OR
H
R'
NaBH4
OC6H11
H
Hg(OTFA)2
OH
OH
Hg(OAc)2
Mukaiyama, Chem. Lett. 1981, 683
Chem 206
COOMe
BnO
Seebach, JACS 1983, 105, 7407
BnOH
NaBH4
COOMe
BnO
OBn
diastereoselection = 83 : 17 (79%)
Oxymercuration Examples
D. A. Evans
Chem 206
Oxymercuration via Hemiketals & Hemiacetals

Proposed Mechanism
J. L. Leighton et. al, Org. Lett. 2000, 2, 3197-3199
! Lewis acid catalyzes formation of hemiketal
! General Reaction: diastereoselection >10:1

R'
OH
OH
Me
HgClOAc
5% Yb(OYt)3
R'
Me
Me
5% Yb(OYt)3
H
R
H
O
! Mechanistic Observations:
O
HgClOAc
Me
Me
acetone, 2h rt
Me
Yb(X
Yb(X
2)2)
HgClOAc
Me
R
Hg
~1:1-mixture of diastereomers
Product formed in low yield.
much recovered starting material
Lewis acid addends were surveyed. the logic for this step was two-fold:
(A) Lewis acid would promote the formation of the putative hemiketal imtermediate.
(B) Lewis acid would promote reversability of the oxymercuration process
X
HgClOAc
Me
O
H
HgCl
low diastereoselectivity
Hg
R
Me
O
Me
O
H
Yb(X2)
O
O
Yb(X2)
Me
Me
H
Me
rate-determining
step
HgCl
Me
H
O
Yb(X2)
"
Me
O
OH
Me
Me
H
O
! The Oxymercuration Step (Kinetic Phase)
Me
5% Yb(OYt)3
Yb(X2)
HgCl
Me
Me
H
OH
HgCl
HgClOAc
Me
Yb(X2)
Leighton presumes that mercurium ion formation is rate-determining

under kinetic conditions. At higher temperatures and longer reaction
times the products are shown to interconvert.
YbX3
OH
Me3C
HgClOAc
5% Yb(OYt)3
O
Me
Me
acetone, 2 min
0 C
Me
Me
ClHg H
Me3C
HgCl
Me
O
HOAc, 5% Yb(OYt)3
Cl
Hg H
Me
Me
Me
MM-2
Me
O
O
Erel = 0
Me
H
Me
O
Me
H
HOAc, 5% Yb(OYt)3
Me
O
Me
Me
Erel = +5.2 kcal/mol
O
Me3C
93% yield
Me
H
YbX3
Cl
Me
O
H
~1:1-mixture of diastereomers
H
Me
Hg
Me
HgCl
O
H
Me
OAc
Me
D. A. Evans
Oxymercuration Examples: X-206 & Lonomycin Syntheses
X-206 Synthesis (with S. Bender, JACS 1988, 110, 2506)

Me
Me
O
Me
OH
Me
OH
OH
OH
O
Me OH Me
Et
O
Me
C1-C16 Subunit
Me
OR
O
OR
Me
OR
O
Me OMe Me
Me
OH
Et
Me
Me
Assemblage strategy for Ring A:
OR
OR
Me
OH
RL
HgX2
RDS
CO2R
RO
Me
Me
H
RL
Me
Me
Me
Me
Me
HO
Me
OH
Me H
Me
Me
OH
OH
O
Me H
RO2C
H
H
R2
OH
consider both (E) & (Z)

olefins
RO2C
Me
H
H
HgX+
H
HO
OR
Me
Me
OH
Me
RDS
H R1
Me
Me
O
Me
Me
H
Me
HO
Me
Hg(OAc)2, CH2Cl2
-78 oC to -20 oC
Me
85%, dr = 93 : 7
RL
Me
BnO
OR
O
O
Me
Me
Hg(OAc)2
CH2Cl2
99%
H
Me
HgX
Me
H R1
16
X
Hg
Me H
OH
H
HO
OR
Me
OH
Me
Predicted stereochemical outcome:
OH
Ionomycin Calcium
Complex
OH
Me
OH
Me
Me
Me
16
Me
Me
Me
Me
OH
Me
Ca
OH
C17-C37 Subunit
Me
Me H
OH
Me
Me
Me
Me
OH
Me
D
aldol
Ionomycin Synthesis (with Dow & Shih, JACS 1990, 112, 5290)
Me
OH
Me
Me
Chem 206
HgX
RL
H
Hg H
X
O
O
Me
Me
XHg
BnO
Me
R2
Me
Me H
O
O
Me
Me
Me
Me
Me
OH
D. A. Evans
Other electrophilic olefin addition reactions afford the same

stereochemical outcome
OH
Hg(OAc)2
Me
RDS
Hg
HO
H
OH
I2, HOAc
n-Bu
Me
RDS
HO
H
OH
Me
I2, HOAc
n-Bu
RDS
HO
H
Me
HCO3
Me
Me
As we have seen before, gauche B

is more destabilizing than gauche A
OAc
Me
CH2
HO
Ratio
96 : 4 (85%) O
Me
O Me
t-BuOOH
VO(acac)2
R = OMe
Me
H
Me
-O2C
K2CO3
MeOH
Ratio = 94 : 6 (85%)
Chamberlin, Tetrahedron 1984, 40, 2297
Me
CH2
HO
HO
Me
O Me
HOAc
n-Bu
H
C
R=H
I
Ratio = 98 : 2 (78%)
n-Bu
-O2C
Me
OH
OAc
n-Bu
Me
I2, HOH/THF
Me
HOAc
HO
RO
HgOAc
n-Bu
OH
OH
ratio = 80 :20
H
Me
Me
OH
n-Bu
n-Bu
OH
Iodine-induced lactonization is also highly stereoselective

! Chamberlin (JACS 1983, 105, 5819)
n-Bu
Chem 206
Related Olefin Addition Rxns: Halogen Electrophiles
OH
MeO
This is an exceptional approach to the creation of either syn or anti

1,3-dioxygen relationships
Me
OH
MeO
Me
Me
Me
Lactonization Ratio = 96 : 4
! Other cases:
Evans, Kaldor, Jones, J. Am. Chem. Soc. 1990, 112, 7001.

TIPSO
OH
TIPSO
OH
O
HO
OH
HO
OH
I2, HOH/THF
Me
Me
HCO3
O H
I2, THF, 4 C
Et
Me
O
HO
Et
0.25 M KH2PO4,
Me
n-Bu3SnH, toluene, 25 C
TsOH, (CH3)2C(OCH3)2, 25 C
I
Me
Me
TIPSO
OH
HO
This methodology superior to oxymercuration

alternative which was evaluated first
67% overall
OH
HO
HO
R = Me: 42 : 58 (81%)
I2, HOH/THF
HCO3
Me
O R
O
Et
Me
R = H: 77 : 23 (74%)
Me
Ratio
>95 : 5 (49%)
I2, HOH/THF
HCO3
Me
R = H: 87 : 13 (41%)
Me
O R
O
R = Me: 90 : 10 (94%)
Halogen-induced heterocyclization in the synthesis of monensin

HO
Me
Me
MeO
B
O
A
O
Me H
C
O
Hypothesis-B:
Stereocontrol through Reversal of Bromonium Ion Intermediate
Me
Et H
D
O
Me
E
O
HO
Me
RL
CH2OH
HO
OH
Me
C
O
Me
Me
NBS
D
OH
Et
Et H
D
O
Me
Br
Me
RL
slow
Me
only one diastereomer
MeCN
57%
Me
C
O
Ar
bromonium ion-olefin exchange
Me
Me
Br
Still, JACS 1980, 103, 2117-2121
! The Kishi Ring D Construction:
fast
RL
Kishi, JACS 1979, 101, 259, 260, 262
Me
Me
Me
Ar
Chem 206
Related Olefin Addition Rxns
D. A. Evans
Ar
RL
OH
Br
Me
C
O
Et H
D
O
Me
Br
Ring D disfavored
! The Kishi Ring D Construction:

! The Still Ring E Construction:
Me
Me
Ar
H
C
O
Me
D
OH
Et
only one diastereomer
MeCN
57%
Hypothesis-A: Stereocontrol
through A(1,3) Strain??
Ar
H
Me
C
O
Et H
D
O
Me
Ar
H
C
O
Et H
D
O
H
OH
Me
RL
Me
D
O
Me
E
O
CH2OH
HO
Me
D
O
D
OH
Me
E
O
I
Ag2CO3
Me
RL
OH
Me
Me
D
Me
Me
M
e
E
HO
Br
DMSO
47%
H
Bromonium ion
formation in RDS
Me
Me
50%
Me
KI3
Me
E
HO
O
HCO3
87%
H Me
KO2_
OH
Me
H
Me
Stereocontrol through A(1,3) Strain??
Me
Me
RL
Me
Me
Me
Me
NBS
Me
Me
D
O
Me
Me
Me
E
I
O
O
Br
RL
El(+)-induced
heterocyclization
Cardillo, Tetrahedron 1990, 46, 3321-3408

Bartlett, Asymmetric Synthesis 1984, 3, Chap 6, 411-454
Applications in Synthesis
D. A. Evans
A complete turnover in olefin diastereofacial selectivity is

observed when adding internal and external nucleophiles
HO
Me
OH
I2
HO
O-
OH
Bu
Me
H2O
General Observation:
OH2
HO
Bu
H
I2
OH
Me
OH
Bu
Me
I
Addition product
Nu
Me
R H
OH
Me
H
O
O
cis : trans 95 : 5
OH
Bu
I2
Me
I
Me
OH
O
Me
HO
Hehre's Analysis
I2
Chem 206
H
HO
Me RDS
R H
H
HO
Favored groundstate conformer
Me
R H
HO
I2
Disfavored !complex
I+
Favored iodonium ion
ratio 99 : 1
For electrophiles that react via onium intermediates (I2, Br2, Hg(OAc)2, PhSeCl),
the major diastereomer from electrophile-induced cyclization is opposite to that
observed in the analogous intermolecular electrophilic addition.
For a review of elctrophilic induced olefin cyclization reactions see:
G. Cardillo & M. Orena, Tetrahedron 1990, 46, 3321.
I2
Me
H H
OH
R
RDS
H H
More reactive
ground-state conformer
Me
H
OH
R
I +
OH
Me
H
Nu
Favored !complex
Disfavored iodonium ion
Chamberlin & Hehre's Rationalization

! "Facial preferences in electrophilic addition reactions are not invariant with respect
to the location of the transition state along the reaction coordinate."
HO
! Change in diastereoselectivity is a consequence of a change in the rate-limiting step
" Cyclization reactions: Intramolecular attack on a !complex (not an onium ion)

! Analysis of the stereoselectivity of electrophilic addition to chiral olefins:
1. Relative abundances of conformational minima
2. Relative reactivities of the available forms
3. Stereoselectivies of the individual conformers
Chamberlin & Hehre, J. Am. Chem. Soc. 1987, 109, 672-677.
I
OH
OH
Me
" Addition reactions: Formation of an onium ion intermediate

(subsequently trapped by a Nu from the medium)
H
O
Bu
Me
I
Cyclization product
Houk: Argument for the "inside alkoxy effect" in !complex formation

! !complex cyclizes if R contains a Nu and its formation is rate determining
! Onium ion formation is rate determing in the addition reactions
! "The presence or absence of an internal nucleophile acts to determine the
stereochemical outcome of the reaction by modifying the nature (timing) of
transition state.
The Simmons-Smith Reaction
D. A. Evans
For a recent general review of the Simmons-Smith reaction see:

Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001)
Chem 206
CH2I2
CH3
Zn-Cu
OH
OH
79 %
M. Pereyre and Co-workers

J. Chem. Res. (S) 1979, 179
Ratio
CH3
Et
tBu
S. Winstein, JACS 1959, 81, 6523; 1961, 83, 3235; 1969, 91, 6892
57
64
67
CH2I2 + Zn
OR
R = OMe: >99:1 Dauben, JACS 1963, 85, 468
CH2I2
CH2
Zn-Cu
R = OAc: 4:1
+ ZnI2
CH2
I
9:1
CH2
OH
ZnI
Enantioselective Simmons-Smith Variants: Kobayashi, Tet. Let. 1992, 33, 2575
CH2I2
Zn-Cu
43
36
33
ICH2ZnI
ICH2ZnI
Sawada, JOC 1968, 33, 1767
OH
OH
:
:
:
The classical mechanism
A large rate acceleration relative to simple olefins was observed.

OR
CH3
OH
>99:1
OH
CH2I2, Zn-Cu
OH
CH3
Et2Zn
CH2OH
PhCH2CH2
CH2I2
CH2OH
PhCH2CH2
80% ee (82% yield)
OH
NHSO2Ar
CH2I2
10 mol%
>99 : 1
CH2
Zn-Cu
Construct a reasonable transition structure which

accomdates the data
NHSO2Ar
OC1C2C3 dihedral = 165
epoxidation also gives anti adduct
These results suggest that the transition state

might be binuclear.
S. Winstein, JACS, 1969, 91, 6892
Low-valent Samarium Variants: Molander,JOC 1987, 52, 3942
Absolute control of stereochemistry is possible through chiral ketal auxiliaries
Me3C
HO
CH2OBn
BnOH2C
> 200 : 1 (99%)
Me3C
Sm or Sm/Hg
R'
BnOH2C
R''
CH3
CH2I2
CH2OBn
OH
R'
R'
R''
R''
O
Me
CH2I2
Zn-Cu
Yamamoto, JACS, 1985, 107, 8254

Mash, JACS, 1985, 107, 8256
Yamamoto, Tetrahedron, 1986, 42, 6458
Me
HO
CH2
Isolated alkenes and homoallylic alcohols
are inert to these reaction conditions.
G. A. Molander and J. B. Etter
J. Org. Chem. 1987, 52, 3942
R''
OH
R'
R"
Ph
Ph
Ph
tBu
tBu
nBu
iPr
tBu
CH3
iPr
OH
Ratio
1
> 200
> 200
1
> 200
:
:
:
:
:
1.4
1
1
5.1
1
D. A. Evans
Chem 206

C. Palomo, "Asymmetric Synthesis of !-Lactams by Stauginger Ketene-Imine

Cycloaddition Reaction, Eur. J. Org. Chem. 1999, 3223-3235.
R
Chemistry 206
N
O
N3
Lecture Number 12
H
C
Correlate with
N3
con
N3 R
R
N
! Electrocyclic Reactions
! Cheletropic Reactions
N3
N3
con
N R
N R

Predict the stereochemical outcome of this reaction.
O
Ph O
Ph
"

O
Ph
Fleming: Chapter 4
"
heat
Huisgen, TL, 1964, 3381.
Ph
Suggest a mechanism for the following reaction.

H
D. A. Evans
CO2Me
Monday,
October 17, 2005
heat
H
MeO2C
CO2Me
Bloomfield, TL, 1969, 3719.
CO2Me
H
Electrocyclic Processes-1
Evans, Breit
Controtation !1 and !2 on to the indicated bonding and anti-bonding

orbitals of cyclobutene:
Electrocyclic Reaction - Selection Rules

Ground State
(Thermal process)
Excited State
(Photochemical Process)
4n ! e(n = 1,2...)
conrotatory
disrotatory
4n+2 ! e(n = 0,1,2...)
disrotatory
conrotatory
Examples
Ground State
LUMO
Con
!2
HOMO
Con
!1
Excited State
Conrotatory
Chem 206
LUMO
HOMO
Disrotatory
Activation Energy (kcal/mol)

for electrocyclic ring opening
Disrotatory
Conrotatory
Conrotatory
Disrotatory
Disrotatory
Conrotatory
Conrotatory
Disrotatory
Conrotatory
Disrotatory
42
45
29
27
H
Disrotatory
Criegee, Chem. Ber. 1968, 101, 102.

Ph O
Con
R
R
Con
Ph
O
O
Ph O
R
Ph
Conrotatory
R
Sterically favored
Ph
Ph
O
O
Ph
Huisgen, TL, 1964, 3381.
Ph
Electrocyclic Processes-2: Torquoselectivity
Evans, Breit
Torquoselectivilty is defined as the predisposition of a given R

substituent for a given conrotatory motion
Houk et al. Acc. Chem. Res 1996, 29, 471
R
H
con
H
in
Donor substituents prefer conout mode

Pi acceptor substituents prefer conin mode
View the 2 conrotatory modes by looking at

the breaking sigma bond from this perspective
con
How do we explain?
Chem 206
out
R

Examples:
R
H
Inward Motion
Outward Motion
R
R
con
H
H
R = Me
R = CHO
CH2OBn
CHO
none
only
only
none
H
H
H
H
H H
H
LUMO + p
LUMO + p
CH2OBn
con
+
H
H
CH2OBn
CHO
H
H
H
H
H
H
H
H H
H
CHO
ratio: >20:1
Me
CN
Me
con
HOMO + p
CN
CN
ratio: 4:1
Me
As conrotation begins the energy of

the breaking sigma bond rises
steeply. Hyperconjugation with a pi*
orbital, while possible in both A & B,
is better in B. (Houk)
HOMO + p
destabilizing 4 electron
interation for donor
substituents
stabilizing 2 electron
interation for acceptor
substituents
Electrocyclic Processes-2: Torquoselectivity
Evans, Breit

How do we explain?
R
View the 2 conrotatory modes by looking at

the breaking sigma bond from this perspective
H
Me
Me
Con-rotation "in"
sterically disfavored.
Chem 206
conrotation
Me
"out"
conrotation
H H
H
Me
"In"
Me
Me
Murakakami Angew. Chem. Int. Ed. 2004, 43, 4873

H
What abut Silyl Substitutents?
Inward Motion
Outward Motion
Me3Si
! 110 C
SiMe3
Me3Si
H H
H
H
H
H
H
H
H
LUMO + p
B
H
H
H
H
H
HOMO + p
As conrotation begins the energy of

the breaking sigma bond rises
steeply. Hyperconjugation with a pi*
orbital, while possible in both A & B,
is better in B. (Houk)
Me3Si
H
LUMO + p
H
H
H H
H
HOMO + p
destabilizing 4 electron
interation for donor
substituents
stabilizing 2 electron
interation for acceptor
substituents
22%
T1/2 = 1.7 hr
H H
"In"
SiMe3
SiMe3
! 110 C
H
Me3Si
SiMe3
78%
Evans, Breit
Electrocyclic Processes-3: 3-Atom Electrocyclizations

Solvolysis of Cyclopropyl Derivatives
Three-Atom Electrocyclizations (2 electrons)

A
H
H
Dis??
H
R
H
A
Con??
Does solvolysis proceed via cation 1 followed by rearrangement to 2

(Case 1), or does it proceed directly to 2 (Case 2)?
Chem 206
Case 1
slow
fast
X
1
2
fast
!3
Case 2
fast
slow
X
+X
nonbonding
Dis
C
Me
40,000
!1
Dis
H
H
Me
Me
Me
Dis
Favored for R = ring
HOMO
LUMO
Me C
R
R
Sterically favored
Me
Me
HOMO
R
R
Me
R
R
X
Dis
Note that there are two disrotatory modes

R
LUMO
TsO
DePuy, Accts. Chem. Res. 1967, 1, 33
Me
C
H
HOMO
!1
Dis
Me
Me
LUMO
anion
cation
TsO
relative rate
!1
!1
TsO
!2
+X
Me
H
Electrocyclic Processes-3: 3-Atom Electrocyclizations
Evans, Breit
Solvolysis Summary
dis-in
dis-out
Unfavorable
favorable
TsO
TsO
H
Me
Me
H
Me
relative rate
Three-Atom Electrocyclizations (4 electrons)

A
TsO
Me
Chem 206
H
H
Dis??
Con??
A
A
A
R
40,000
Ring-fused Cyclopropyl Systems

When the cis substiltutents on the cyclopropyl ring are tied together
in a ring the following observsations have been made
TsO
TsO
H
nonbonding
!2
H
!3
!1
favored
H2C
H
H
TsO
(CH2)2
H
TsO
disavored
!2
Con
H2C
O
base
Observation
Ar N
Cl
disallowed
H CO2Me
Con
H
CO2Me
Ar N
products
MeO2C
CO2Me
Ar N
(+)
()
MeO2C
H CO2Me
3-exo-tet
dis-in
Cl
B
C
dis-out
C
R
Revisiting the Favorski rearrangement: (Carey, Part A, pp 506-8)

Cl
anion
cation
dis-in
relative rate: > 10+6
MeO2C
Con
Ar N
(+)
MeO2C
()
Electrocyclic Processes-3
Evans, Breit
Chem 206
Five-Atom Electrocyclizations (4 electrons)
The Nazarov Reaction

O
R
Dis??
R
Con??
OH
+H+
H+
A
Denmark, S. E. In Comprehensive Organic Synthesis; Trost, B. M.,

Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5; pp 751.
O
!3
+H+
predict
stereochemistry
H
!2
Eight-Atom Electrocyclizations (8 electrons)
!1
Dis??
Anion
Cation
Pentadienyl Cation
A
!2
nonbonding
LUMO
Con
A
Con??
A
H
HOMO
C
A
Let's use the "Ready" shortcut to find the homo: Nodes will appear at
single bonds
symmetry of homo
Pentadienyl Anion
A
LUMO
!3
Dis
H
HOMO
C
A
C
A
!4
Closure should be conrotatory
Database Problems on Electrocyclic Processes
D. A. Evans
Problem 122. The interesting transformation illustrated below was recently reported by F.
West and co-workers (Org. Lett. 2001, 3, 3033-3035). The pivotal reaction upon which this
transformation was designed is a pericyclic process that affords a pivotal element of
stereocontrol.
OMe
O
O
Me
OMe TiCl , CH Cl
4
2 2
Me
!
!
Et
78C, 5 min
!
Et
Me
!
99% yield
Problem 215. Provide a mechanism for the following set of transformations (J. Org. Chem.
1999, 64, 2170). It should be noted that compound A exhibits a strong carbonyl frequency in
the infrared spectrum. Clearly indicate the structure of compound A and the relative
stereochemistry of any chiral intermediates.
OMe
OMe
MeO
Me
OH
Ph
O
Me
CH2OR'
Me
n-Bu
Li
3
Me
Me
SO2Ph
78*" rt
Ph
n-Bu
72% yield
SO2Ph
O
Problem 780. Santilli and co-workers reported this Lewis acid catalyzed reaction (Santilli etal.
JACS 1991, 113, 8062-8069). Please provide a reasonable mechanism for this transformation
that includes the rationalization of the stereochemical outcome of the transformation.
O
O
Me
Me
Me
Cl
Me
Part B. Provide a mechanism for the transformation of 3 to 4. Classify all pericyclic

processes should they intervene.
Me Me
Me
Me
Me
heat
heat
CO2H
Problem 736. Please provide a mechanism for the following transformation recently reported
by Magomedov and co-workers (JACS 2004, 126, 16265) This is one of seven cases
reported. Be sure to classify any pericyclic processes that intervene.
Part A. Provide a mechanism for the transformation of 1 to 2. l represents an 18O label.

Classify all pericyclic processes should they intervene.
O
"
Ph
Ph
Me
Problem 161. The following transformations entail an "apparent" methyl migration.

Address the questions posed below.
endiandric acid B
MeO
Provide a concise mechanism for this reaction in the space below.
Ph
CH2OR'
O
"
Ph
OH
MeO
73 %
Ph
RO
120C
Me
! 80C
Problem 718. Black proposed that the biosynthesis of endiandric acid B involved a series of
pericyclic reactions beginning with the given acyclic starting material. Propose a mechanism for
this transformation. You may find it helpful to start with the product and work backwards. Hint:
The last step of this mechanism is a Diels-Alder reaction.
compound A
C28H28O3
CO2H
O
Me
C C OMe
2) acidic workup
MeOH
HO
Mycophenolic Acid
RO
OMe
Li
C15H20O4
Part B. Provide a mechanism for the overall transformation. Since stereochemical issues
are at stake, carefully rendered 3-D conformational drawings should be incorporated into
your answer.
Problem 158. Danheiser and coworkers ( JACS 1986,
108, 806) have described an innovative synthesis of the
antifungal agent mycophenolic acid. The crucial reaction
which resulted in the assemblage of the highly
substituted phenolic ring is provided below.
Ph
OMe 1)
Me
Part A. Identify the pericyclic process that intervenes in the illustrated transformation and
illustrate the relative configuration(s) stereocenter(s) that are generated.
Chem 206
Me
AlCl3
60% yield
Et
H
Me
Cheletropic Processes-1
Evans, Breit
Chem 206
CHELETROPIC REACTIONS: [n+1] Cycloadditions (or Cycloreversions)

Concerted processes in which 2 !-bonds are made (or broken) which terminate at
a single atom.
2 + 1 CheletropicReaction: Olefins + Singlet Carbene

R
[4+2]
+
C
R
Linear Approach: 2 HOMO-LUMO Interactions
S
O
General
R
R
X
Z
Reversion
!-system
!-system
C
Y
Addition
R
R
HOMO
LUMO
LUMO
HOMO
Nonlinear Approach: 2 HOMO-LUMO Interactions
Y
C
Z
[4+1]
Singlet-Carbene
Addition (and Reversion)
Frontier Orbitals
sp2 (filled) !2
N N
C O
N N O
Reversion
and Addition
Cycloreversion only
!0
p (empty)
R R
SO2
R R
E
!0
LUMO
HOMO
!2
X
Z
Carry out the analysis of the indicated hypothetical transformation

Me
Me
Y
Question: what is orientation of carbene

relative to attacking olefin??
LUMO
HOMO
R
C
R
Z
Me
Me
predict approach geometry of carbene
D. A. Evans
A Carbene Cycloaddition
Chem 206
Problem 726. A [4+1] cycloaddition between a diene and a carbene has recently been reported by
Spino and co-workers (JACS, 2004, 126, 9926).
Part A. Using a Dewar-Zimmerman or an FMO analysis, determine if this reaction is thermally allowed.
Be sure to consider both the approach and the geometry of the carbene carefully.
R
HOMO
LUMO
LUMO
HOMO
FMO Analysis
R
Part B. Provide a mechanism for the following reaction reported by Spino.

MeO2C
CO2Me
Me N N OMe
Me
O
retro
[3+2]
Me
Me
OMe
O
OMe
PhCl, reflux
OMe
MeO
H
CO2Me
CO2Me
H
H H
H H
N2
OMe
CO2Me
Me
Me
CO2Me
OMe
O
[4+1]
MeO
H
H
CO2Me
H
most stable TS
has cis ring fusion
O
H
H
CO2Me
H
Cheletropic Processes-2
Evans, Breit
Chem 206
Key step in the Ramberg Bcklund Rearrangement
Let's now consider SO2 as the one-atom component
R1
R2
R1
E
O
O
R1
O
4e in pi system
!1 filled
!2 filled
!3
R2
base
R1
empty
R2
Me
R1
R2
Z
-SO2
Clough, J. M. The Ramberg-Backlund Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon
Press: Oxford, 1991; Vol. 3, pp 861.
"The Ramberg-Backlund Rearrangement.", Paquette, L. A. Org. React. (N.Y.) 1977, 25, 1.
suprafacial
R2
base
S
Me
-SO2
S
O
Me
Me
Me
Me
reactions are:
stereospecific & reversible
Analysis of the Suprafacial SO2 Extrusion (nonlinear)
suprafacial
R1
R1
SO2
R2
Me
Me
O
S
O
S
HOMO
R2
!3
O
O
HOMO
!3
empty (LUMO)
empty (LUMO)
O
O
S
LUMO
!2 filled
O
O
LUMO
!1 filled
Similar to carbene geometry
S
O
D. A. Evans
Chem 206

[2,3] Sigmatropic Rearrangements

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapter 4.6:
Chemistry 206
Nakai, T.; Mikami, K. Org. React. (N.Y.) 1994, 46, 105-209.

Hoffmann, Angew. Chem. Int. Ed. 1979, 18, 563-572 (Stereochemistry of)
Nakai, Chem. Rev. 1986, 86, 885-902 (Wittig Rearrangement)

Evans, Accts. Chem. Res. 1974, 7, 147-55 (Sulfoxide Rearrangement)
Vedejs, Accts. Chem. Res. 1984, 17, 358-364 (Sulfur Ylilde Rearrangements)
Lecture Number 13
! Introduction to Sigmatropic Rearrangements
! [2,3] Sigmatropic Rearrangements
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,

Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
Chapter 7.2, Claisen
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)
Paquette, L. A. (1990). Stereocontrolled construction of complex cyclic
ketones by oxy-Cope rearrangement. Angew. Chem., Int. Ed. Engl. 29: 609.

Fleming: Chapter 4

Provide a mechanism for this transformation.
Me
Me
Me
Me
Me
D. A. Evans
Wednesday
October 19, 2005
heat
PPh3
S=PPh3
Me
Me
Me
For study on this [2,3] rxn See Baldwin JACS 1971, 93, 6307
Sigmatropic Rearrangements-1
D. A. Evans
Sigmatropic rearrangements are those reactions in which a sigma bond

(& associated substituent) interchanges termini on a conjugated pi system
! Examples:
[1,3] Sigmatropic rearrangement
! [1,3] Sigmatropic Rearrangements (C migration)

X
CH3
consider the 1,3-migration of Carbon
Y:
:X
Retention at carbon
Inversion at carbon
antibonding
C
bonding
bonding
Consider the orbitals needed to contruct

the transition state (TS).
Y
H
X
Sychronous bonding to both termini

is possible from this geometry
[1,3]-Sigmatropic rearrangements are not common

no observed scrambling of labels
! Construct TS by uniting an allyl and H radical:

bonding
antibonding
Y !2 (allyl HOMO)
bonding
Suprafacial Geometry
"
Me
Me
Antarafacial Geometry
Bridging distance too great for antarafacial migration.
!
"
C
H
! The stereochemical constraints on the suprafacial migration of carbon

with inversion of configuration is highly disfavored on the basis of strain.
bonding
H X
X
Sychronous bonding to both termini

cannot be achieved from this geometry
X
C R
H
! [1,3] Sigmatropic Rearrangements (H migration)

H
Construct TS by uniting an allyl and Me radicals:
X
H
H3
C
bonding
Consider the orbitals needed to contruct

the transition state (TS).
X
consider the 1,3-migration of H
CH3
Chem 206
Me
120 C
1
These rearrangements are only seen in systems that are highly strained,
an attribute that lowers the activation for rearrangement.
Sigmatropic Rearrangements-2
D. A. Evans
SIGMATROPIC REACTIONS - FMO-Analysis

2
4
3
!/h"
! [1,5] Sigmatropic Rearrangements (C migration)
4
5
R = H, CR3
Chem 206
[1s,5s] alkyl shift ! RETENTION
! [1,5] Sigmatropic Rearrangements (H migration)
[1a,5a] alkyl shift ! INVERSION

disfavored
!4
! [1,5] (C migration): Stereochemical Evaluation
!3
nonbonding
Me
5
h"
3
!2
Me
RETENTION
230-280C
Me
H
[1,5s]C- shift
Me
[1,5s]H- shift
Me
Me
DewarZimmerman Analysis: Retention
!1
thermal
photochemical
R
H
View as cycloadditon between following species:

R
R
H
suprafacial preferred
R
H
H
H
H
+
R
pentadienyl radical !3
either, or
H
R
the transiton structure
0 phase inversions ! Huckel toplogy

6 electrons
therefore, allowed thermally
Sigmatropic Rearrangements: An Overview
D. A. Evans
The Wittig Rearrangement [1,2]
[1,2] Sigmatropic Rearrangements: Carbon

[1,2]-Sigmatropic rearrangements to cationic centers allowed.
Wagner-Meerwein Rearrangement
R
Chem 206
"[2,3]-Wittig Sigmatropic Rearrangements in Organic Synthesis.", Nakai,

T.; Mikami, K. Chem. Rev. 1986, 86, 885.
Marshall, J. A. The Wittig Rearrangement.; Trost, B. M. and Fleming, I.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 975.
Li
O
consider as cycloaddition
BuLi
Ea ~16 Kcal/mol
FMO analysis
!
R!
This 1,2-sigmatropic
rearrangement is nonconcerted
R
Li
O
R
olefin radical cation
The Wittig Rearrangement [2,3]
transition state
[1,2]-Sigmatropic rearr to carbanionic centers not observed

R
!!
stepwise
!!
concerted
O
!!
R
OLi
FMO analysis
consider as cycloaddition
FMO analysis
antibonding
!
!!
!!
!!
ketyl radical
!!
H
transition state
R
H
R
olefin radical anion
R
!
Allyl radical
transition state
The !!G between concerted and nonconcerted pathways can be quite small
Li
[2,3]-Sigmatropic Rearrangements: An Introduction
D. A. Evans
" The basic process:

R2
R
R3
R2
R
R3
:X
Y:
Me
R2
R
:X
temp
Me
R3
Me
Me
Me
Me
Me
Me
Me
Me
25 C
Rautenstrauch, Chem Commun. 1979, 1970
X & Y = permutations of C, N, O, S, Se, P; however X is usually a heteroatom
Me
OH
BuLi
Me
Chem 206
Me
Me
OH
Me
~70%
M
e
~30%
! X - S, Y = C; Sulfonium Ylide Rearrangement:
Attributes: Stereoselective olefin construction & chirality transfer

[2,3]
BuLi
! Representative X-Y Pairs:
SP, SN, SO (sulfoxides)

OP
(phosphites)
+
NN, Cl C (haloium ylids)
PC, CC (homoallylic anions).
NO (amine oxides)
SC (sulfur ylids)
OC (Wittig rearrangement)
NC (nitrogen ylids)
SS (disulfides)
S
S
Li+
S
Lythgoe, Chem Commum 1972, 757
! X - N, Y = C; Ammonium Ylide Rearrangement:
An important early paper: Baldwin, J. Chem. Soc., Chem. Comm. 1970, 576
Sommelet-Hauser:
! General Reviews:
Me
Me
Me
BuLi
O
Ph
BuLi
Ph
Me
[2,3]
Me
LiO
Ph
Me
CH2 NMe2
Me
NMe2
Me
R2
Ph
R1
Li
O H
Ph
Li
Me
R
Ph
Garst, JACS 1976, 98, 1526
R2
R3
Me N
Li+
Me
CH2
Modern versions of Stevens:
Baldwin, JACS 1971, 93, 3556

[1,2]
base
Review, Pines, Org. Rxns 1970, 18, 416
Li+
Ph
Me
Me
! X - O, Y = C; Wittig Rearrangement:
Me
[2,3]
BuLi
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapter 4.6:

Nakai, T.; Mikami, K. Org. React. (N.Y.) 1994, 46, 105-209.
Hoffmann, Angew. Chem. Int. Ed. 1979, 18, 563-572 (Stereochemistry of)
Nakai, Chem. Rev. 1986, 86, 885-902 (Wittig Rearrangement)
Evans, Accts. Chem. Res. 1974, 7, 147-55 (sulfoxide Rearrangement)
Vedejs, Accts. Chem. Res. 1984, 17, 358-364 (Sulfur Ylilde Rearrangements)
BuLi
R1
Me N
CN
R2
R3
[2,3]
R1
R3
Me
Me2N
CN
CN
Buchi, JACS 1974, 96, 7573

Mander, JOC 1973, 38, 2915
important extension lacking CN FG; Sato, JACS 1990, 112, 1999
[2,3]-Sigmatropic Rearrangements: Introduction-2
D. A. Evans
! X - O, Y = C; Wittig-like Rearrangements
R2
R1
R3 140 C
OH
R2
R2
R3
OMe
H
" X - S, Y = O; Sulfoxide Rearrangement
R2
R1
R1
+ NMe2
NMe2
OMe
R3
R1
NMe2
Ar
+
S
R2
R2
R2
R2
R1
R3
R1
Ar
R3
O
N
R2
R3
+
Se
R1
Se
Ts
Ar
Smith, Chem. Commun. 1974, 695; Smith, JOC 1977, 42, 3165
R2
R1
selenophile R1
R3
NHTs
Ts
Hopkins, Tet Let. 1984, 25, 15

Hopkins, JOC 1984, 49, 3647
Hopkins, JOC 1985, 50, 417
! X - S, Y = N; Related Rearrangement
R3
Na+
TsNCl
TsO
[2,3]
TsO
OR
! X - N, Y = O; Meisenheimer Rearrangement
R3
R1
R3
Me
N
Ts
Ph
R2
R2
Me
R3
ROH
note that the product contains the retrons

for the enolate Claisen rearrangement
R2
!
Me N
R3
OH
BuLi
PhSCl
Ar
N2
" X - Se, Y = N; Related Rearrangement
R1
! X - O, Y = C; An all-carbon Rearrangement
R1
thiophile
R1
Evans, Accts. Chem. Res. 1974, 7, 147
In thinking about this rearrangement,

also consider the carbenoid resonance
form as well
C:
NMe2
R3
keq < 1
R2
R1
R3
O
R3 Cu(I)
R2
R3
Buchi, JACS 1974, 96, 5563
R2
R1
R1
Chem 206
TsO
Ts N
SPh
(MeO)3P
NaOH
Ph
R2
Zn/HOAc
R1
R3
85% yield overall
OH
Me
Tanabe, Tet Let. 1975, 3005
N
Ts
Dolle, Tet Let. 1989, 30, 4723
TsO
N
Ts
[2,3]-Sigmatropic Rearrangements: Olefin Geometry
D. A. Evans
! 1,2-Disubstitution: Good Trans Olefin Selectivity

Starting olefin: Trans
favored
(E) selectivity: "only isomer"
:X
Me
Ph
Ph
Rb
Rb
Rb
Me
HO
Ra
Ra
RLi
-75 to -50 C
Ra
Me
Chem 206
2 LDA
-75 to -50 C
Me
(E) selectivity: 75%

HO
Y:
Ra
H
disfavored
Rb
H
Ra
Y
:X
Y
Rb
R1
S
Ar
Starting olefin: Cis
favored
Ra
Rb
:X
Rb
Y:
OH
(E) selectivity: >95%
Ar
Evans, Accts. Chem. Res. 1974, 7, 147-55

O
The preceeding transition state models do not explain some of the results:
! Cis selectivity has been observed: Still JACS 1978, 100, 1927.
Rb
Me
Ra
R2
R2
Rb
highly
disfavored
R1
MeOH
H
H
R2 (MeO) P
3
Ra
Ra
R1
RLi R1X
Ar
Nakai, Tet. Lett 1981, 22, 69

R2
Ra & Rb prefer to orient in pseudo-equatorial positions during rearrangement;

nevertheless, this is a delicately balanced situation
CO2H
CO2H
Rb
H
Y
H
Ra
Y
:X
SnBu3
Conclusions
! (Z) Olefin rearrangements might exhibit higher levels of 1,3 induction
OH
R
ratio, 65:35
Bu3Sn
Me
n-BuLi
-78 C
R
Me
OH only (E) isomer

(91%)
Several theoretical studies have been published: Good reading
! Product olefin geometry can be either (E) or (Z) from (E) starting material
! Product olefin geometry will be (E) from (Z) starting material
Me
! However, Cis selectivity is dependent on starting olefin geometry

R
! Olefin geometry dictates sense of asymmetric induction in rearrangement
Me
n-BuLi
-78 C
Houk JOC 1991, 56, 5657 (Sulfur ylide transition states)

Houk JOC 1990, 55, 1421 (Wittig transition states)
O
H
D. A. Evans
Chem 206
! (Z) selectivity has been observed: Still JACS 1978, 100, 1927.
! Starting olefin: (E) Trisubstituted
Me
favored
favored
Me
R1
X
Y
Y:
Me
SnBu3
(E)-path
:X
R2
H2C
Y
H
Me
Me
n-Bu
H
H
Li
LiO
Me
R1
Y
:X
C4H9
CH2Li
(Z)-path
R2
H
halogen
CH2
R2
R1
C4H9 Me
H2C
highly
disfavored
SnBu3
OH
n-Bu
R1
R2
n-Bu
Still says that the TS is early, so that the 1,2 interactions in the TS are
most important.
destabilizing
Me
R2
R1
n-BuLi
-78 C
Me
Me
Me
KH
R1Me interaction can destabilize the (E) transition state while (Z) TS might
be destabilized by R1 interactions with both X-Y and allyl moiety.
" Starting olefin: (Z)
Li
n-Bu
R1
Y
:X
Me
R2
Me
R2
95%, >96% (Z)
n-Bu
Me
R1
disfavored
R2
:X
Y:
OH
n-Bu
R1
R2
X
Me
R2
Me
R1
Me
R1
Li
Me
Me
R1
CH2
LiO
! (Z) selectivity has also been observed by others: Sato JACS 1990, 112,
1999.
Me
Me
LHMDS, NH3
NMe2
-70 C
Conclusions
! Olefin geometry dictates sense of asymmetric induction in rearrangement
Me N +Me
Me
XMe
! (Z) Olefin rearrangements might exhibit higher levels of 1,3 induction

! Product olefin geometry can be either (E) or (Z) from (E) starting material
! Product olefin geometry will be (E) from (Z) starting material
76%, (Z):(E) 95:5

NMe2
CsF in HMPA
Me N +CH TMS
2
- Me
25 C
Me
61%, (E):(Z) 100:0
D. A. Evans
! Trisubstituted olefins via [2,3]-rearrangement of sulfonium ylides:
Trisubstituted olefins via [2,3]-rearrangement of sulfoxides:

PhS
(E)-path
Me
favored
Me
Me
R1
H
Ph
Ph
S
(Z)-path
Ph
disfavored
R1
Me
CuSO4
100 C
N2 C(COOMe)2
Bu
CO2Me
S CO2Me
Ph +
CO2Me
Ph
A general procedure for the direct synthesis of sulfur ylides:
Ph
Me
Me
R
S
R
R
+S C
R
R
+ :CR2
Me
base
n-BuLi
S
N
N
N
N
Me
S Li
Br
Me
Me
!/" = 90:10 (95%)
Me
! Trisubstituted olefins via Wittig [2,3]-rearrangement:

Me
RCO3H
Accts. Chem. Res. 1974, 7, 147-55
Me
"
Me
Me
C5H11
Me
(E):(Z) > 97:3 (80-85%)
Et2NH, MeOH
25 C
Me
S
N
Me
N
N
Me
C5H11
(E):(Z) > 95:5 (74%)

HO
Me
CO2H
[2,3]
OH
()
Me
2 LDA
Me
Me
R
R
+S C H
R
R
pKa ~ 18 (DMSO
!
!
CO2Me
(E):(Z) > 90:10 (70%)
! In contrast to the previous cases exhibiting (Z) selectivity rearrangements

(E)-selective rearrangments has been observed:
Me
Me
Bu
Me
R1
Me
Bu
R1
Ar
Me
R1
Chem 206
Me
CO2H Nakai, Tet Let 1981, 22, 69
However, this reaction is not general:

O
Me
Me
Me
LDA
(E):(Z) 31:69
Me
is operationally
equivalent to:
Me
HO
()
H
OH
CO2Me
CO2Me
Nakai, Tet Let 1986, 27, 4511
D. A. Evans
! Trisubstituted olefins via [2,3]-rearrangement:
(E)-path
Me
RL
RM Y
:X
RM
H
Me
S
Me
Me
For study on this [2,3] rxn See

Baldwin JACS 1971, 93, 6307
(RL = large)
X
Me
Me
RM
RL
RL
An elegant squalene synthesis Ollis, Chem. Commun 1969, 99
Me
Y:
RL
(Z)-path
X
Y
RM
RM
Me
RL
Me
Me
heat
[2,3]
Me
Me
S
Me S
Me
Me
minor constituent in equil
Me
:X
PPh3 ! S=PPh3
One might project that the (E) path will be moderately favored with selectivity
depending on size difference between RL & RM
Me
Me
Me
n-BuLi
Me
Me
Me
Me
Me
Me
+
S
Me
Me
Me
Me
Me
Me
[2,3]
Me
NMe2
OMe
Buchi, JACS 1974, 96, 5563
Me
Me
For related [2,3] rxns See

SPh
Me
Me
Me
Me
Me
140 C
OMe
Me
Ph
This rxn is probably not as

stereoselective as advertised
(E):(Z) = 3:2
Me
Me
Me
SLi
Me
OH
F
MgBr
Me
Me
Me
benzyne
Me
Rautenstrauch, Helv. Chim Acta 1971, 54, 739
C:
Li/NH3
O
Me
Me
NMe2
Me
poorly selective
Me
Me
Me
"gave one major product in high yield"
NMe2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Li
Me
Me
Me
Me
Me
Me
Squalene
Me
Me
Me
[2,3]-Sigmatropic Rearrangements: Chirality Transfer
D. A. Evans
[2,3] Sulfur Ylide Rearrangement Using a Chiral Auxiliary
Chem 206
Chiral Auxiliaries can also be used in the Wittig Rearrangement
Kurth JOC 1990, 55, 2286 and TL 1991, 32, 335

Me
Me
Me
CO2H steps
Me
CO2H
Me
NH2
BuLi
Allylation
Me
SH
96% de (61%)
CH2OR
CO2H
XC
HO
ROCH2
Me
steps
Me
Me
Me
DBU, -78 C
Me
HBF4
CH2Cl2
O
S+
Me
BF4 -
Me
Cp2ZrCl2
CH2OR
O
O
Me
BuLi
97% syn; 96% de

XC (43%)
HO
Me
Katsuki, Tet Lett 1986, 27, 4577
ROCH2
N2
Internal Relay of Stereochemistry in CC Constructions

Me
Me
Me
Me
O
S+
Me
O
Me
Me
Bu3Sn
Me Me
C3H7
O
Me
Me
Me Me
Me
C3H7
Me
Me
O
S+
Me
O
S
O
S
n-BuLi, THF, -78 C
OBOM
Kallmerten TL 1988, 29, 6901.
Me
Me
C3H7
OH
OBOM
diastereoselection > 100:1 (64%)
Me
Me
Me
Me
OBOM
diastereoselection > 100:1 (57%)

Bu3Sn
Me
C3H7
OH
Me
66%, 94:4
Me
Me
n-BuLi, THF, -78 C
OBOM
Me
Me
Me
64%, 4:93
See these papers for other applications

Kallmerten SynLet 1992, 845.
D. A. Evans
Internal Relay of Stereochemistry in CO Constructions

Tandem [ 4+2 ] & [ 2,3 ] Process:
Cases where the chirality is exocyclic to the rearrangement
Evans, Bryan, Sims J. Am. Chem. Soc. 1972, 2891.
Me
Ph
!
N
S Me
O
Ph
n-BuLi
Me
ratio 79 : 6
HO
HO
SnBu3
Na2S, MeOH
HO
O
Me
Me
O
N
Me
OMe
MeO
Me
Me
Chem 206
A Felkin analysis predicts the

major product
H2C
O
O
C
HO
Bruckner, Angew. Chem. Int. Ed. 1988, 27, 278

N
cepharamine
Me
H
O
N
Me
C5H11
15
Allylic Ethers to Make Three Contiguous Stereocenters
O
CO2Et
HSPh, KOt-Bu
CO2Et
H
C5H11
TBSO
Me
TBSO
15
SPh
OH
n-BuLi, -78 C
SPh
1) MCPBA
94%
Me
TMS
TMS
2) P(OMe)3
TBSO
O
CO2H
C5H11
OH
steps
CO2Et
15
Nakai TL, 1988, 29, 4587.
C5H11
OH
Me
4%
TMS
OH
Can you rationalize the stereochemical outcome of this reaction?
Taber J. Am. Chem. Soc. 1977, 99, 3513.

Kondo Tet. Lett. 1978, 3927.
D. A. Evans
The Synthesis of Bakkenolide-A

Me
O
(Evans JACS 1977, 99, 5453)
Me
Me
HO
C: H
Me3C
Me
OH
R3
O
OMe
H
R3
C:
NMe2
NMe2
R3
C
N
R3
NaH
65 C
SMe
Baldwin, Chem Comm 1972, 354
Me
Me
Me
selectivity: 90:10
CN
Mander, JOC, 1973, 38,

2915
S
Note that rearrangement is not required to proceed
via the carbenoid. propose altenate mechanism
Me
H
Me
H
NaH
65 C
SMe
O
heat
NHTs
Me
Me
Me
NHTs
OEt
selectivity: 52:48
Me
Me3C
CMe3
O
H
heat
S
65% (no other isomer)
OEt
Br
Me
H2SeO3
Me3C
! The comparison of analogous [2,3] & [3,3] rearrangements:
HO
HgCl2, HOH MeS
-10 C
CMe3
O
MgBr
Me
Me
Me
Bakkenolide-A
OH
H
selectivity: 92:8
Evans, JACS, 1972, 94,
3672
C CN
H
Me3C
OSPh
SMe
! The synthesis:
Me
Me
Me3C
CMe3
SMe
NHTs
25 C
(MeO)3P
MeOH
R3
C:
CO2Et
CMe3
Ph
Buchi, JACS 1974, 96, 5563
selectivity: 91:9
CMe3
NMe2
SPh
Me3C
C
H CO2Et
Cu(I) catalysis
25 C
OMe
+ Ph
S
N2=CHCO2Et
140 C
X: favored
Y
H
Ph
! Candidate processes:
R3
Me3C
:Y
Me
CH2
Me
HO
[2,3] Sigmatropic rearrangements respond to subtile steric effects
Me
Me
Chem 206
selectivity: 75:25
Me3C
H
SMe
CMe3
House, JOC 1975, 40, 86
[2,3]-Sigmatropic Rearrangements: Ring Expansion & Contraction
D. A. Evans
Ring expansion reactions have been investigated
Chem 206
A ring contraction using the Wittig Rearrangement

Me
Methods based on sulfur ylides: (review) Vedejs, Accts. Chem. Res. 1984, 17, 358
Me
Me
R2NLi
Cu(O)
+S
TfO
KOt-Bu
S
+
50%
CO2Et
CO2Et
N2
Me
CO2Et
Me
Me
HO
Li
N
Ph
With chiral amide Ph
bases induction
is observed!
Me Me
CO2Et
Me
72%
DBU
82%, 69% ee
Aristolactone
72%
EtO2C
Me
Marshall, JACS 1988, 110, 2925
Me
O
OH Methynolide has been synthesized by Vedejs
using this ring-expansion methodology
Me
HO
Me
Et
Me
A ring contraction using the Stevens Rearrangement
Vedejs, JACS 1989, 111, 8430

Me
Me
An early ring expansion using the Sommelet-Hauser Rearrangement
Me
Me
+
N
MeO
Ph
NaNH2
+
N
Me
Me
liq NH3
Me
Br
N
Me
nonselective
N-alkylation
Ph
Me
Me
+
N
Me
Me
78%
MeOH
Ph
Me
N
Me Ph
Both rearrangements afford a single isomer
Me
MeO
O
Me
Hauser, JACS 1957, 79, 4449
Ph
salts readily separated
83%
N
Me
Me
Me
N+
CH2
54%
MeOH
Me
Me
Me
D. A. Evans
Chem 206


Chemistry 206

Lecture Number 13
! [3,3] Sigmatropic Rearrangements: Introduction
! Cope Rearrangements & Variants
! Claisen Rearrangements & Variants
Paquette, L. A. (1990). Stereocontrolled construction of complex cyclic

ketones by oxy-Cope rearrangement. Angew. Chem., Int. Ed. Engl. 29: 609.

Predict the stereochemical outcome of this Claisen rearrangement
Et
Et
O

Fleming: Chapter 4: Thermal Pericyclic Reactions
diastereoselection
>87:13
144 C, 6h
CMe3
CMe3
Ireland, JOC 1983, 48, 1829
K. Houk, Transition Structures of Hydrocarbon Pericyclic Rxns

Angew Chem. Int. Ed. Engl. 1992, 31, 682-708
K. Houk, Pericyclic Reaction Transition States: Passions & Punctilios, Accts.
Chem. Res. 1995, 28, 81-90
Angew Chem. Int. Ed. Engl. 1992, 31, 682-708
Provide a mechanism for the indicated fransformation

OH
O
Me
D. A. Evans
Friday,
October 21, 2005
Me
KH, ! THF
H3O+ quench
Me
H
Me
Schreiber, JACS 1984, 106, 4038
Database Problem number 117: Key words: Rearrangement + Claisen

In a recent article, MacMillan and Yoon (JACS 2001, 123, 2448) reported the complex rearrangement illustrated below.
R2N
O
R2N
Cl
Me
Me
several equiv
Me
Yb(OTf)3
CH2Cl2, R3N
R2N
NR2
Me
Me
diastereoselection >95:5
Part A. Provide a mechanism for this overall transformation. In answering this question, you should illustrate
those transition states where stereocenters are generated and where stereochemcal information is relayed.
Part B. From your answer in Part A, illustrate the stereochemical relationships in the diamide product A.
Database Problem number 195: Key words: Rearrangement + Claisen

Provide a mechanism for the indicated transformation that accounts for the observed stereochemical outcome
(JACS, 1984, 7643).
O
SAr
O
Cl
S
O
C O
Ar
Cl
H Cl Cl
D. A. Evans
Introduction to [3, 3]-Sigmatropic Rearrangements
Chem 206
General Reviews:
The CopeTransition States
Relative Energy !!G:
CHAIR
BOAT
+ 5.8 kcal/mol
CHAIR
BOAT
+ 5.3 kcal/mol
X & Z = C, O, N etc
Relative Energy !G:
The Boat and Chair geometries for these transition structures are well defined.
Cope Rearrangement, Ea = 33.5 kcal/mol
Claisen Rearrangement Ea = 30.6 kcal/mol
The Reaction Energetics Goldstein, JACS 1972, 94, 7147
The FMO Analysis (Fleming page 101)

Bring two allyl radicals together to access for a possible bonding interaction
between termini.
!G523 = 46.3
!G523 = 40.5
The nonbonding
allyl MO
!2
X
bonding
bonding
It is evident that synchronous bonding is possible in this rearrangement
Chem 206
The DoeringRoth Experiments
D. A. Evans
Doering/Roth Experiments: Tetrahedron 18, 67, (1962):

The Geometry of the transltion state (boat vs chair) can be analyzed via
the rearrangement of substituted 1,5-dienes:
The Results
favored
Me
Me
Me
Me
Me
Me
Threo isomer
Me
Results:
Threo isomer
Me
H less favored
Me
Me
Me
Me
trans-trans:
90%
Me
Me
H
H
Me
Me
Me
Me
H disfavored
Me
Me
Me
cis-cis:
10%
trans-cis:
< 1%
Me
Meso isomer
Me
! Measure product composition from rearrangement of each diene isomer

H
favored
Me
Me
trans-trans
Me
H
Me
Me
Predictions:
Threo isomer
H less favored
H
Me
H disfavored
trans-cis
Me
Predictions:
Meso isomer
favored
Me
H
trans-trans: 0.3%
Me disfavored
H
Brown Chem. Commun. 1973, 319

CHAIR
Relative Energy !!G:
BOAT
+ 5.8 kcal/mol
Vogel Annalen 1958, 615, 1
H
CHAIR
H
Relative
60
C Energy !G:
Me trans-trans
H
120 C
trans-cis
Me
Me
Me
H
5-20 C
Me
Me
Me
!!G
~ 5.7 kcal/mol
disfavored
Me
trans-cis: 99.7%
The CopeTransition
Ring Strain can be employed
to drive theStates
Cope process:
H
Me
cis-cis
Me
Me
Me
H
Me
favored
Me
H
H
Me
H
Results:
Meso isomer
Me
Me
Me
BOAT
+ 5.3 kcal/mol
Reese Chem. Commun. 1970, 1519
The Boat and Chair geometries for these transition structures are well defined.
equilibrium stongly favors this isomer
D. A. Evans
Chem 206
StrainAccelerated Cope Rearrangements
Ring Strain can be employed to drive the Cope process:
! Ring extension via divinylcyclopropane rearrangement

O
20 C
Me
"quantitative"
Me
Me
I
(PhS)Cu
W. von E. Doering's Bullvalene
90%
Me
1.5 equiv
Li+
O Me Me
heat
xylene
Me
Me
LDA
Me
!
MeI
O
(EtO)2P
Me Me
Me
Li
Me
At 100 C one carbon is observed in nmr spectrum
Me
(Ph3)3RhCl
LDA
! Position of Equilibrium dictated by ring strain issues:
Me
CO2Et
Wittig
+ S(O)Me2
H
H
CO2Et
Me
60-70%
Marino, J. Org. Chem. 1974, 39, 3175
Accelerated Cope Rearrangements
Wharton J. Org. Chem.

1973, 38, 4117
H
Me
140 C
CHO
Vogel Angew. Chem. Int. Ed.

1963, 2, 739
Piers, Can J. Chem. 1983, 61, 1226, 1239
Me
Me
(EtO)2PCl
Me
!-himachalene
Carey, Vol 1, page 630631
O Me Me
H2
EtNH2/THF
Bullvalene: Ea = 13.9 kcal/mol
favored
O Me Me
HO
! However, tautomerism can shift the equilibrium:
k1
HO
HO
H
keq ~ 10+5
220 C
3h
OH
OH
90%
Marvell, Tet. Lett. 1970, 509

Energetically, how much does
tautomerization give you?
keq ~ 10+5
!G = 1.4(pKeq) = 1.4X(-5) = -7 kcal/mmol
k2
k2
= 10 + 10
k1
10 + 17
Evans, Golob, JACS 1975, 97, 4765.

"Recent applications of anionic oxy-Cope rearrangements."
Paquette, L. A. Tetrahedron 1997, 53, 13971-14020
D. A. Evans
Chem 206
The Anionic Oxy-Cope Rearrangement
Documentation of Alkoxy Substituent Effect
The Aborted Oxy-Cope Reaction (circa 1969)

! The basic reaction
OX
OX
OH
Me
OH
Me
OX
66 C
THF
Me
H
H
MeO
! Actual case studied:

Me
Me
OH
Me
Me
Me
Prediction of Substituent Effect (circa 1969)
HO
HO
!GOH
pka (SM)
Me
OLi
no rxn
ONa
1.2 hrs
OK
1.4 min
OK
11 hrs
O- +K
4.4 min
66 C
(HMPT)
10 C
XO
66 C
THF
No Rxn
!!Gestimate = 15 kca mol -1

!!Gexperiment = 13 kca mol -1
MeO
!GOH
Origin of the Rate Effect
pka (TS)
!GO
HO
!GO
??
Effect probably comes from both

reactant destabilization
&
transition state stabilization
!GO = !GOH + 2.3RT [ pka TS pka SM]
!GO = !GOH
(66 yrs)
Me
Me
Me
4
6
10 +12 rate acceleration
OH
HO
OH
OMe
Half-life
!GO = !GOH +
2.3RT [18 29] (in DMSO)
HO
"
" !
~ 15 kcal/mol
1.4 [ 11]
!GO = !GOH 15 kcal/mol at 298 K (in DMSO)
Maximal rates are observed under conditions where reactant is maximally destabilized
D. A. Evans
Chem 206
Anionic Substituent Effects: Bond Homolysis
Substituent Effects in Bond Homolysis

HO C CR3
DI
HO C
DI!I
+ CR3
O C
+ CR3
HO C
H
(H2O) pKa = 10.7
[2,3]
X
R
Ph
X
R
[1,3]
X Y
X Y
DI DII = 2.3 RT [pka (A) pka (B)]

Acidities of these radicals are
HO C known in H2O, Hayon, Accts.
Chem. Res. 1974, 7, 114
ketyl
[3,3]
A
O C CR3
Substituent Effects in Molecular Rearrangements
[1,2]
ene
HO C
Ph
pKa = 9.2
Y X
Y X
In DMSO, D = 2.3 RT [ 29 18] ~15 kcal/mol

Y X
Y X
! Substituent Effect based on ab initio calculations

(Evans, Goddard, JACS 1979, 101, 1994)
H
HO C H
H
BDE = 90.7
(BDE = 91.8 expt)
H
NaO C H
H
BDE = 80.6
KO C H
O C H
H
BDE = 79.0
H
BDE = 74.2
!D
+16.5 kcal/mol
C
X
X C
X C
RH
X C
X C
D. A. Evans
MeO
Chem 206
Anionic Oxy-Cope Rearrangement: Applications
OMe
MeO
OMe
O
NaH
OH
OMe
H
OMe
Me
H2C
H
Me
OH
OR
Jung, JACS 1978, 100, 4309

Jung, JACS 1980, 102, 2463
KH, THF
O Levine, JOC 1981, 46, 2199
KH
Me
ROH2C
OH
200 g from 75,000

virgin female cockroaches
Me
Me
Periplanone-B Synthesis
75%
MgX
Me
! THF
Me
ROH2C
Me
Still, JACS 1979, 101, 2493

OH
OR
Me
OH
KH
Me
KH, THF
Me
Me
Gadwood, JOC, 1982, 47, 2268
Me
Me
! THF
Me
Me
2 steps
Schreiber, JACS 1984, 106, 4038
Me
H
Synthesis of (+)-CP-263,114: Shair, JACS 2000, 122, 7424-7425.

O
HC CLi
50 C
OH
Me
Me
Me
O
CO2H
MeO2C
XMgO CH OR
2
H
Me
poitediol
Me
Me
H
Me
dactylol
Me
Me
Gadwood, JACS, 1986, 108, 6343
OMe
R
H
Me
Me
OH
OH
OH
Me
50 % yield
Me
OH
O
O
[3,3]
78!23 C
H
R
O
R
H
XMgO CH OR
2
R
H
53%
Dieckmann
CH2OR
Me
D. A. Evans
The Claisen Rearrangement
! General Reviews:
Chem 206
Recognition Pattern for Organic Synthesis: An Enforced SN2'

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2
Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen)
Bennett, Synthesis 1977, 589 (Claisen)
Blechert, Synthesis 1989, 71 (HeteroCope)
R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)
Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)
Claisen
SN2'
! The Reaction:
#H ~ 20 kcal mol-1
Stereochemical outcome is syn and controlled by hydroxyl stereocenter
R
1 O
There is good thermodynamic driving force for this reaction.

Bonds Broken: C-C! (65 kcal mol-1) & C-O" (85 kcal mol-1)
Bonds Made: C-O! (85 kcal mol-1) and C-C" (85 kcal mol-1)
X
O
! Themodynamics of Claisen Variants:

X
X=H
X = OH
X = NH2
1 O
!H (kcal mol-1)
Substituent
16
31
30
77%
~ 20
~ 20 kcal/mol
OH
H
180-200 oC
Rearrangements of Aryl Allyl Ethers: Traditional Applications
OR
Control of stereocenter 2 evolves into a decision how to

establish the hydroxyl-bearing stereocenter
~ 30
(Benson estimates)
Me
Me
Me 180-200
oC
Me
Me
Me
OH
O
Cope Me
Me
Me
Me
~ 30 kcal/mol
OR
91%
Me
O
Heteroatom substitution at the indicated position increases

exothermicity as well as reaction rate
Me
65%
OH
Me
Me
E:Z = 6.7:1
The Claisen Rearrangement-2
D. A. Evans
Synthesis of Allyl Vinyl Ethers
! Endocyclic Olefins: Ireland, JOC 1983, 48, 1829

Et
Hg(OAc)2
OH
O
Et
144 C, 6h
OEt (solvent)
Watanabe, Conlon, JACS 1957, 79, 2828

Bronsted acids can also serve as catalysts
CMe3
R
B
Me3C
H
H2C
H2C
Cp2Ti
AlMe2
H
H2C
The Ireland approach to the bicyclic acid A:
X
Me
O
O
Me3C
Me
Me
HO
HO
Me
ratio 52:48
H
H
H
Me
OH
Me
Me
Me OH
Me
EtOCH=CH2
O
O
Me3C
Me3C
Me
Me
Me
OEt Me3C
H
OH
Me
X=H
HO
OEt
Me
Claisen
JOC 1962, 27, 1118
OEt
heat
96%
(review) S. H. Pines, Organic Reactions 1993, 43, 1
Me3C
! Exocyclic Olefins: House, JOC 1975, 40, 86
CMe3
O
Cl
heat
Ph
Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272.
Me3C
C
Ph
CH2
CMe3
CH2
For endocyclic olefins, overlap between developing sigma and pi bonds required. Best
overlap for forming chair geometry. As shown below, bring a radical up to either face
of the allylic radical. As the bond is formed, overlap must be maintained. Path A
evolves into a chair conformation while Path B evolved into a boat conformation.
75%
OEt
CH2
-EtOH
AcOHg
diastereoselection
>87:13
Me3C
Chem 206
ratio 75:25
for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good
from either olefin diastereoface. In this instance, steric effects dominate & this system
shows a modest preference for "equatorial attack." A related case is provided below.
HH
Hg(OAc)2
HO
Me
Me
53% overall
HO
Me
Me
H !
O
H
The new stereocenter (!) introduced via the rearrangement had

the wrong configuration!
D. A. Evans
Claisen Rearrangement as vehicle for stereoselective olefin synthesis

Consider the following rearrangement:
Faulkner suggests that the installation of other substituents on Claisen

transition states will lead to enhanced reaction diastereoselection:
ke
ke
CHO
Me
ka
Me
Me
!Ga - !Ge = 1.5 kcal/mol
Me
Me
CHO
Me
ka
Me
H
#Note:
!!G = +1.5 kcal/mol
!G = +1.75 kcal/mol
They then suggest that there is a good correlation between cyclohexane "A-values" &
!!G for the rearrangement process. Their case is fortified by the following expamples:
CHO
110 C
R2
R1 (E)
R1
R2
Me
Me
Et
Et
iPr
Et
(E):(Z) found
90:10
93:07
90:10
O
X
R2
Me
as X gets progressively larger.
(E):(Z) found
Me2N
>98:2
Faulkner, Tet Let 1969, 3243

Faulkner, JACS 1973, 95, 553
Johnson, JACS 1970, 92, 741
! Another comparison: (DAE) M. DiMare, Ph. D. Harvard University, 1988

X
OY
Et
OPMB
Me
Et
CHO
R2
R1
91:9
94:6
91:9
Faulkner, JACS 1973, 95, 553
Me
O
X
(Z)
(E):(Z) predicted
(Z)
a
90:10
>99:1
>99:1
R2
R1
Me
H
For R2 = Et Me
MeO
The A-value of 2-methyl-tetrahydropyran is +2.86 kcal/mol (Lecture No. 6)
Me
(E)
R2
Me
Me
The R2!X interaction should destabilize
Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between
!!G for rearrangement & !G for the corrresponding cyclohexane# equilibria:
R2
R2
110 C
R2
110 C
Me
Me
Chem 206
The Claisen Rearrangement: Stereoselective Olefin Synthesis
OPMB
Et
procedure
Y = Ac, Ireland
Y = H, Johnson
Y = H, Eschenmoser
conditions
Me
LDA, TMSCl
HC(OMe)3, H+
TMSO
MeO
MeC(OMe)2NMe2
Me2N
T, C
(E):(Z) ratio
-78!+55
130
80
97:3
94:6
97.5:2.5

Organic Chemistry

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Welcome to Chem 206

Fall Term, 2005, David A. Evans

Problems for this course may be accessed at the following website:

Web Problems (>500)

An Introduction to Frontier Molecular Orbital Theory-1

! Problems of the Day

Advanced Organic Chemistry

Introduction to FMO Theory

This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in

! General Bonding Considerations

(First hr exam, 1999)

! Reading Assignment for week:

Kirby, Stereoelectronic Effects

Carey & Sundberg: Part A; Chapter 1

Fleming, Chapter 1 & 2

An Introduction to Frontier Molecular Orbital Theory-1

Universal Effects Governing Chemical Reactions

! General Reaction Types

molecular orbital (LUMO) in reacting species is very important

the highest filled (HOMO) and lowest unfilled (antibonding)

Polar Reactions (~90%):

! Electronic Effects (Inductive Effects):

FMO concepts extend the donor-acceptor paradigm to

rate decreases as R becomes more electronegative

"Organic chemists are generally unaware of the impact of

Steric Versus Electronic Effects; A time to be careful!!

! Steric Versus electronic Effects: Some Case Studies

Danishefsky et al JOC 1991, 56, 387

Mehta et al, Acc Chem. Res. 2000, 33, 278-286

The H2 Molecular Orbitals & Antibonds

Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients

The H2 Molecule (again!!)

! Rule one: A linear combination of n atomic states will create n MOs.

"# = C*1!1 C*2!2

The coefficients, C1 and C2, represent the contribution of each AO.

" = C1!1 + C2!2

The squares of the C-values are a measure of the electron population

In LCAO method, both wave functions must each contribute

Note that #E1 is greater than #E2. Why?

! Bond strengths (Bond dissociation energies) are composed of a

(Fleming, page 27)

! Orbital orientation strongly affects the strength of the resulting bond.

When one compares bond strengths between CC and CX, where X

Useful generalizations on covalent bonding

This is a simple notion with very important consequences. It surfaces

! Anti orientation of filled and unfilled orbitals leads to better overlap.

H3CSiH3 BDE ~ 70 kcal/mol

! Weak bonds will have corresponding low-lying antibonds.

Case-2: Two anti sigma bonds

This trend is even more dramatic with pi-bonds:

H3CCH3 BDE = 88 kcal/mol

Case-1: Anti Nonbonding electron pair & CX bond

Hyperconjugation, The Anomeric Effect, and More

Useful LIterature Reviews

Kirby, A. J. (1982). The Anomeric Effect and Related Stereoelectronic Effects at

Advanced Organic Chemistry

Box, V. G. S. (1998). The anomeric effect of monosaccharides and their

Juaristi, E. and G. Cuevas (1992). Recent studies on the anomeric effect.

Carey & Sundberg: Part A; Chapter 3 pp 151-156

! "Positive" and "Negative" Hyperconjugation

Question: First hour Exam 2000 (Database Problem 34)

! Peracid & Dioxirane Epoxidation (Stereoelectronics)

Kirby, Stereoelectronic Effects Chapters 1-5

"# = C1!1 C2!2