D. A.

Evans

Hyperconjugation, The Anomeric Effect, and More

Chem 206

Useful LIterature Reviews

http://www.courses.fas.harvard.edu/colgsas/1063

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.

Advanced Organic Chemistry

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

Database problem 307

! Anomeric and Related Effects

! Peracid & Dioxirane Epoxidation (Stereoelectronics)

Kirby, Stereoelectronic Effects Chapters 1-5

Natural bond order (NBO) analysis is a powerful computational tool that allows
one to quantitatively estimate the energy of hyperconjugative effects (Alabugin
& Zeiden, JACS 2002, 124, 3175). The stabilizing interactions for the H1 and
H4 equatorial hydrogens for 1,3-dioxane and 1,3-dithiane are provided below.
It is interesting that the two indicated hyperconjugative interactions in dioxane
are approximately the same (4.5 vs 4.2) but that the same interactions in
dithiane are quite different (6.5 vs 1.8). In fact, the authors refer to CS bonds
as "one directional" acceptor orbitals.

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

+4.2

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

Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)

H4

H1
O

+4.5
!CH " !*CO

D. A. Evans

Wednesday,
September 20, 2006

numbers refer to interaction

energies in kcal/mol at the
B3LYP/6-31+G*** level

+1.8
S

H4

H1
S

+6.5
!CH " !*CS

There is one quite reasonable qualitative argument that can rationalize the
"one directional" character of !*CS. Please provide your argument in the
space provided below.

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

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.

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

Stereoelectronic Requirement for Hyperconjugation:

100.6

1.608

Me

Syn-planar orientation between interacting orbitals

Me
Me

The Molecular Orbital Description

!" CR

!" CR

+
C

T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349

H
H

The Adamantane Reference

(MM-2)

1.528

! CR

! CR

110
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."

Me
Me

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

note labeled oxygen is transferfed

chiral catalyst

O-O bond energy: ~35 kcal/mol

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.

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)