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K. A.

Scheidt Chem 413


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Course Overview
Texts: Strategic Applications of Named Reactions in Synthesis, Krti & Czak. roLecung Croup ln Crganlc SynLhesls,
Creene and WuLs, Wlley 3rd Ld. Both texts are primarily reference.
Course Description: This course covers the rst half of advanced organic chemistry and focuses on tactics/
reactions in modern synthetic chemistry.
Ofce Hours: By appointment. scheidt@northwestern.edu
Teaching Assistant: Ben McDonald, email: ben[amln.mcdonald[norLhwesLern.edu
Class Schedule: Classes meet three days a week (MWF, 9-10 am). Lectures may be held during reading week. Recitation/
problem session with TA (day and location TBA). Class days may be moved due to unavoidable KAS travel schedule: watch
for announcements.
Evaluation: There are three exams (100 pts each) and nal team project (100 pts) for a total of 400 points.
There are no make-up exams. Unexcused exam absences will count as zero points. In the case of an excused
absence, a student will receive a grade that is the average of the 2 other exams..
Final Project: Topic selection due date: October 18th, 5:00 pm. !"#$%&#"' )* +,&-. -/ '+%+//&0*.
1-'&. 20"3+%45 6+&,/ 7-.. )+ &//-8'+9 )* :;< = >?@A
B+/%0-C#"'5 Choose from Lhe llsL of Loplcs presenLed ln 1
sL
week of CcLober. llnal lvoL olnL" pro[ecL enLalls Leam presenLauons durlng 8eadlng Week of
appllcauons/dlscoverles relaLed Lo class maLerlal. lace emphasls/address how Lhe Loplc moved Lhe eld forward and changed collecuve Lhlnklng. More
deLalls wlll be forLhcomlng- Lhe lnLegrauon of 1/keynoLe and Chemdraw ls requlred and LemplaLe les for each program wlll be provlded.
FMO/Stereoelectronic Effects
Olen Addition Reactions
Olenation Chemistry
Carbanions
Pericyclic Reactions
Oxidations
Reductions
Protecting Groups
Carbonyl/Azomethine Additions
Aldol Reactions
Carbonium Ions
Organosilicon Chemistry
Hydrazone Methodology
Metal free Catalysis
Peptide couplings
Course
Topics
all rights reserved
Chem 413
Modern Organic Synthesis
TARGET
STRATEGY
TACTICS
retro-
synthesis
strategy
realization
actual
synthesis
Total number of steps
Convergent vs. Linear approach
Key bond forming reactions
Functional group manipulation
Protecting group scheme
Stereoselectivity (ee, dr)
Cannot understand/create/execute strategies without
broad knowledge of tactics
K. A. Scheidt Chem 413
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Frontier Molecular Orbital Theory
Chemistry 413
Advanced Organic Chemistry
Lecture Number 1
Frontier Molecular Orbitals
why do they matter?
Wednesday
September 25, 2013

General bonding consideration review

The H2 Molecule Revisited

Donor & Acceptor Properties of Bonding &


Antibonding States

Hyperconjugation and "Negative" Hyperconjugation

Anomeric and Related Effects


! Reading Assignment:
Fukui, Acc. Chem. Res. 1971, 4, 57.
Kishi, J. Am. Chem. Soc. 1998, 120, 9392.
Juaristi, J. Am. Chem. Soc. 2002, 124, 13088.
Deslongchamp, Org. Biomol. Chem. 2011, 9, 5321.
! Problems of the Day
Use FMO to explain the reduction of uoroadamantanone A
Lactone 2 is signicantly more susceptible to nucleophilic
attack at the carbonyl carbon than 1? Explain.
Lactone 2 is signicantly more prone to enolization than 1?
In fact the pKa of 2 is ~25 while ester 1 is ~30 (DMSO). Explain.
2
1
versus
O
O
Et
O
O
Me
le Noble, W. J. J. Am. Chem. Soc. 1995, 117, 7088
O
F F
NaBH
4
HO H
F
H OH
60% 40%
A
K. A. Scheidt Chem 413
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Introduction to FMO Theory
minor
major
Br:

Nu:
Nonbonding interactions (Van der Waals repulsion) between
substituents within a molecule or between reacting molecules
!Steric Effects
Universal Effects Governing Chemical Reactions
There are three:
C Br
Me
R
R
C
R
R
Me
Nu
RO
H
S
N
2
O
Me
2
CuLi
RO
H
O
H
Me
RO
H
O
Me
H
+ Br:

!Electronic Effects (Inductive Effects):


+
S
N
1
rate decreases as R becomes more electronegative
C
R
R
Me
Br C Me
R
R
Inductive Effects: Through-bond polarization
Field Effects: Through-space polarization
A bizarre contra-steric transformation:
Danishefsky, JOC 1991, 56, 387
Lewis acid
diastereoselection >94 : 6
O
OSiR
3
OSiR
3
OSiR
3
EtO
2
C
R
3
SiO
EtO
"During the course of chemical reactions, the interaction of
the highest lled (HOMO) and lowest unlled (antibonding)
molecular orbital (LUMO) in reacting species is very important
to the stabilization of the transition structure."
Geometrical constraints placed upon ground and transition states
by orbital overlap considerations.
!Stereoelectronic Effects
Fukui Postulate for reactions:
!General Reaction Types
Radical Reactions (~10%): A B + A B
Polar Reactions (~90%): A(:) B(+)
+ A B
Lewis Base
Lewis Acid
FMO concepts extend the donor-acceptor paradigm to
non-obvious families of reactions
!Unusual examples
H
2
2 Li(0) +
CH
3
I Mg(0) +
CH
3
MgBr
2 LiH
K. A. Scheidt Chem 413
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FMO Laureates
Kenichi Fukui Roald Hoffmann
The Nobel Prize in Chemistry 1981
"for their theories, developed independently,
concerning the course of chemical reactions"
Kyoto University Cornell University
A Claim on the Development of the Frontier Orbital Explanation of Electrocyclic Reactions
Hoffmann, R. Angew. Chem. Int. Ed. 2004, 43, 6586 6590
Controversy regarding this discovery
Note: R. B. Woodward passed away July 8, 1979
K. A. Scheidt Chem 413
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Hydrogen Orbitals
+ C
1
!
1
" = C
2
!
2
Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients
Each MO is constructed by taking a linear combination of the
individual atomic orbitals (AO):
Bonding MO
Antibonding MO
C*
2
!
2
"# =C*
1
!
1

The coefficients, C
1
and C
2
, represent the contribution of each AO.
! Rule Three: (C
1
)
2
+ (C
2
)
2
= 1
= 1 antibonding(C*
1
)
2
+ bonding(C
1
)
2
! Rule Four:
E
n
e
r
g
y
$# (antibonding)
$ (bonding)
Consider the pi -bond 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.
C
C
O
C O
The squares of the C-values are a measure of the electron
populationin neighborhood of atoms in question
In LCAO method, both wave functions must each contribute
one net orbital
! Rule Two:
O
The H
2
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:
E
n
e
r
g
y
1s 1s
!" (antibonding)
! Rule one: A linear combination of n atomic states will create n MOs.
#E
#E
Note that #E
1
is greater than #E
2.
Why?
! (bonding)
! (bonding)
#E
2
#E
1
!" (antibonding)
1s 1s
$
2
$
2
$
1
$
1
E
n
e
r
g
y
H H
H H
K. A. Scheidt Chem 413
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Bond Generalizations
!Weak bonds will have corresponding low-lying antibonds.
! SiSi = 23 kcal/mol ! CSi = 36 kcal/mol ! CC = 65 kcal/mol
This trend is even more dramatic with pi-bonds:
"# CSi
"# CC
" CSi
" CC
Bond length = 1.87 Bond length = 1.534
H
3
CSiH
3
BDE ~ 70 kcal/mol H
3
CCH
3
BDE = 88 kcal/mol
Useful generalizations on covalent bonding
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.
Bond Energy (BDE) = $ E
covalent
+

$ E
ionic
!Bond strengths (Bond dissociation energies) are composed of a
covalent contribution ($ E
cov
) and an ionic contribution ($ E
ionic
).
better than
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.
!Overlap between orbitals of comparable energy is more effective
than overlap between orbitals of differing energy.
Formation of a weak bond will lead to a corresponding low-lying antibonding
orbital. Such structures are reactive as both nucleophiles & electrophiles
C-SP
3
Si-SP
3
C-SP
3 C-SP
3
Si C Si C C C C C

Better
than
Better
than
Case-2: Two anti sigma bonds
! CY
HOMO
!* CX
LUMO
!* CX
LUMO
lone pair
HOMO
!* CX
LUMO
!* CX
LUMO
lone pair
HOMO
Case-1: Anti Nonbonding electron pair & CX bond
!An anti orientation of filled and unfilled orbitals leads to better
overlap.

This is a corrollary to the preceding generalization.
There are two common situations.
Better
than
For " Bonds:
For ! Bonds:
!Orbital orientation strongly affects the strength of the resulting
bond.
Better
than
! CY
HOMO
A C A C
C C C C
A C
X
A
Y
C
X
A B
A B
Y
Y
X X
X X
B A
B
A
K. A. Scheidt Chem 413
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Donor/Acceptor Properties of Bonding & Antibonding States
! !
"
C
SP3
-C
SP2
is a better acceptor orbital than !
"
C
SP3
-C
SP3
C-SP
3
C-SP
3
!* CC
! CC
C-SP
3
! CC
!* CC
C-SP
2
Donor Acceptor Properties of C
SP3
-C
SP3
& C
SP3
-C
SP2
Bonds
! The greater electronegativity of C
SP2
lowers both the bonding &
antibonding CC states. Hence:
! ! C
SP3
-C
SP3
is a better donor orbital than ! C
SP3
-C
SP2
! !
"
CO is a better acceptor orbital than !
"
CC
! ! CC is a better donor orbital than ! CO
! The greater electronegativity of oxygen lowers both the bonding
& antibonding C-O states. Hence:
Consider the energy level diagrams for both bonding & antibonding
orbitals for CC and CO bonds.
Donor Acceptor Properties of C-C & C-O Bonds
O-SP
3
!* C-O
! C-O
C-SP
3
! C-C
!* C-C
better donor
better acceptor
Following trends are made on the basis of comparing the bonding
and
antibonding states for the molecule CH
3
X where X = C, N, O, F, & H.
Hierarchy of Donor & Acceptor States
decreasing donor capacity
Nonbonding States
poorest donor
The following are trends for the energy levels of
nonbonding states of several common molecules. Trend
was established by photoelectron spectroscopy.
best acceptor
poorest donor
Increasing !
"
-acceptor capacity
!-anti-bonding States: (CX)
!-bonding States: (CX)
decreasing !-donor capacity
CH
3
CH
3 CH
3
H
CH
3
NH
2
CH
3
OH
CH
3
F
CH
3
H CH
3
CH
3
CH
3
NH
2
CH
3
OH
CH
3
F
HCl:
H
2
O:
H
3
N:
H
2
S:
H
3
P:
K. A. Scheidt Chem 413
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Hyperconjugation: Carbocations
+
+
+
+
+
+
C C
R
H
H
H
H
C
H
H
C
H
H
R +
C
H
H
C
H
H
The new occupied bonding orbital is lower in energy. When you
stabilize the electrons is a system you stabilize the system itself.
Take a linear combination of ! CR and CSP
2
p-orbital:
! CR
!" CR
! CR
!" CR
The Molecular Orbital Description
Syn-planar orientation between interacting orbitals
Stereoelectronic Requirement for Hyperconjugation:
The graphic illustrates the fact that the C-R bonding electrons
can "delocalize" to stabilize the electron deficient carbocationic
center.
Note that the general rules of drawing resonance structures still
hold: the positions of all atoms must not be changed.
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.
First X-ray Structure of an Aliphatic Carbocation
Bonds participating in the hyperconjugative interaction, e.g. CR,
will be lengthened while the C(+)C bond will be shortened.
Physical Evidence for Hyperconjugation
First X-ray Structure of an Aliphatic Carbocation
Bonds participating in the hyperconjugative interaction, e.g. CR,
will be lengthened while the C(+)C bond will be shortened.
Physical Evidence for Hyperconjugation
For adamantane synthesis, see: Schleyer, P. von R.; Donaldson, M. M.; Nicholas, R.
D.; Cupas, C. (1973), "Adamantane", Org. Synth.; Coll. Vol. 5: 16
Adamantane Xray:
Laube, Angew Chem. Int. Ed. 1986, 4, 349
1.431
1.608
100.6
K. A. Scheidt Chem 413
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Negative Hyperconjugation
As the antibonding CR orbital
decreases in energy, the magnitude
of this interaction will increase
! CR
!!
!" CR
The Molecular Orbital Description
" Delocalization of nonbonding electron pairs into vicinal antibonding
orbitals is also possible
X
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.
C X
R
H
H
H
H
X
H
H
C
H
H
R
!!
This decloalization is referred to as "Negative" hyperconjugation
Nonbonding e

pair
!!
Note that ! CR is slightly destabilized
antibonding !" CR
! Overlap between two orbitals is better in the anti
orientation!!!!
+

Anti Orientation
filled
hybrid orbital
filled
hybrid orbital
antibonding !" CR
Syn Orientation

+
C X
H
H
C X
H
H C
H
C
H
H
R
X
H
R
X
C X
H
H
C X
H
H
R:
R:
""
""
""
""
R
R
NMR Spectroscopy ! Greater e-density at R
! Less e-density at X NMR Spectroscopy
! Longer CR bond X-ray crystallography
Infrared Spectroscopy ! Weaker CR bond
! Stronger CX bond Infrared Spectroscopy
X-ray crystallography ! Shorter CX bond
Spectroscopic Probe Change in Structure
The Expected Structural Perturbations
K. A. Scheidt Chem 413
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Lone Pair Delocalization
(LUMO)
!" NH
Fact, the gauche conformation is favored. Hence we have neglected
an important stabilization feature in the structure.
Hydrazine can exist in either gauche or anti
conformations (relative to lone pairs).
The interaction of filled orbitals with adjacent antibonding orbitals
canaffect conformation. This is called the gauche effect.
Theory: the anti isomer should be more stable than the gauche isomer.
Hydrazine
!" NH
(LUMO)
filled
N-SP
3
(LUMO)
!" NH
filled
N-SP
3
! NH
! NH
HOMO-LUMO Interactions
Orbital overlap between filled (bonding) and antibonding states is
best in the anti orientation. HOMO-LUMO delocalization is possible
between: (a) N-lone pair # !" NH; (b) ! NH # !" NH
better stabilization
anti gauche
observed HNNH
dihedral angle Ca 90
N N
H
H
H
H
N N
N N
N
H
H
H
N
H
H H
H H
!!
!! !!
!!
H
H
H
Examples
(HOMO)
(HOMO)
(HOMO)
(HOMO)
The closer in energy the HOMO and LUMO the better the resulting
stabilization through delocalization.
!N-lone pair ! "# NH delocalization better than
" NH ! "# NH delocalization.
!Hence, hydrazine will adopt the gauche conformation where both
N-lone pairs will be anti to an antibonding acceptor orbital.
The trend observed for hydrazine holds for oxygen derivatives as well
Hydrogen peroxide
gauche
anti
H
2
O
2
can exist in either gauche or anti
conformations (relative to hydrogens).
The gauche conformer is prefered.
! Major stabilizing interaction is the delocalization of O-lone pairs into
the CH antibonding orbitals (Figure A). Note that there are no such
stabilizing interactions in the anti conformation while there are 2 in the
gauche conformation.
observed HOOH
dihedral angle Ca 90
(LUMO)
"# OH
filled
O-SP
3
filled
O-SP
3
!Note that you achieve no net stabilization of the system by generating
molecular orbitals from two filled states (Figure B).
Figure A Figure B
O O
H
H
H
H
O
H
O
H
""
""
""
"" ""
""
""
""
(HOMO)
(HOMO)
K. A. Scheidt Chem 413
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The Anomeric Effect
The Anomeric Effect
It is not unexpected that the methoxyl substituent on a cyclohexane ring
prefers to adopt the equatorial conformation.
! G = +0.6 kcal/mol
! G = 0.6 kcal/mol
What is unexpected is that the closely related 2-methoxytetrahydropyran
prefers the axial conformation:
H
OMe
H
OMe
OMe
H
OMe
H
O
O
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.
axial O lone pair"#$ CH axial O lone pair"#$ CO
Principal HOMO-LUMO interaction from each conformation is
illustrated below:
O
H
OMe
O
H
OMe
Let anomeric effect = A
! G
p
= ! G
c
+ A
A = ! G
p
! G
c

A = 0.6 kcal/mol 0.6 kcal/mol = 1.2 kcal/mol


!!
!!
Better Acceptor!
Useful LIterature Reviews on Anomeric Effect
Kirby, A. J. (1982). The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen. New York, Springer Verlag.
Graczyk, P. P. and M. Mikolajczyk (1994). Anomeric effect: origin and
consequences. Top. Stereochem. 21: 159-349.
Juaristi, E. and G. Cuevas (1992). Recent studies on the anomeric effect.
Tetrahedron 48: 5019.
Thatcher, G. R. J., Ed. (1993). The Anomeric Effect and Associated
Stereoelectronic Effects. Washington DC, American Chemical Society.
Freitas, M. P. (2013). The anomeric effect on the basis of natural bond orbital
analysis. Org. Biomol. Chem. 11, 2885-2890
The Exo-Anomeric Effect
H
O
O
R
! 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
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
K. A. Scheidt Chem 413
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Anomeric Effect: Carbonyl Groups
Do the following valence bond resonance structures
have meaning?
C
R
O
X
!!
!!
C
R
O
X
!!
!!

+
Prediction: As X becomes more electronegative, the IR frequency
should increase
1720 1750 1780
!
C=O
(cm
-1
)
Me CH
3
O
Me CBr
3
O
Me CF
3
O
Prediction: As the indicated pi-bonding increases, the XCO
bond angle should decrease. This distortion improves overlap.
C
R
O
X
!!
"* CX #O lone pair
C
R
O
X
!!
Evidence for this distortion has been obtained by X-ray crystallography
Corey, Tetrahedron Lett. 1992, 33, 7103-7106
! CH = 3050 cm
-1
! CH = 2730 cm
-1
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.
C
H
C
R
O
H
C
R R
R
!!
!!
Sigma conjugation of the lone pair anti to the H will weaken the bond.
This will result in a low frequency shift.
filled
N-SP
2
Infrared evidence for lone pair delocalization into
vicinal antibonding orbitals.
! NH = 2188 cm
-1
! NH = 2317 cm
-1
filled
N-SP
2
antibonding
"# NH
..
antibonding
"# NH
The NH stretching frequency of cis-methyl diazene is 200 cm
-1
lower
than the trans isomer.
N N
Me H
N
H
N
Me
N N
Me
N
N
Me
!! !!
!!
!!
" 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.
H
H
K. A. Scheidt Chem 413
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Orbital Effects in Esters/Acids
! Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridization
is driven by system to optimize pi-bonding.
The filled oxygen p-orbital interacts with pi (and pi*)
C=O to form a 3-centered 4-electron bonding system.
SP
2
Hybridization
The oxygen lone pairs conjugate with the C=O.
! Lone Pair Conjugation:
C O
O
R
R

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.
(E) Conformer
In the (E) conformation this
lone pair is aligned to overlap
with !* CR.
!* CR
!* CO
In the (Z) conformation this
lone pair is aligned to overlap
with !* CO.
(Z) Conformer
! Hyperconjugation:
Let us now focus on the oxygen lone pair in the hybrid
orbital lying in the sigma framework of the C=O plane.
C
R
O
R
O
R O
R
O
R
C O
O R
R
O
O
R

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).
!G = +2 kcal/mol
Specic Case:
Formic Acid
(E) Conformer (Z) Conformer
! Conformations: There are 2 planar conformations.
O
O
R'
R R O
R'
O
O
O
H
H H O
H
O
barrier ~ 10
kcal/mol
!G ~ 2-3
kcal/mol
E
n
e
r
g
y
These resonance structures suggest
hindered rotation about =COR bond.
This is indeed observed:
+
! Rotational Barriers: There is hindered rotation about the =COR bond.
R O
R'
O O
O
R'
R
R O
R
O
O
O
R
R
C O
O
R
R
Lactone 2 is signicantly more prone to enolization than 1?
In fact the pKa of 2 is ~25 while ester 1 is ~30 (DMSO). Explain.
2)
1) Lactone 2 is signicantly more susceptible to nucleophilic
attack at the carbonyl carbon than 1? Explain.
Esters strongly prefer to adopt the (Z) conformation while small-ring lactones
such as 2 are constrained to exist in the (E) conformation. From the
preceding discussion explain thefollowing:
2
1
versus
Esters versus Lactones: Questions to Ponder.
O
O
Et
CH
3
CH
2
O
O

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