Hyperconjugation refers to stabilization that occurs through overlap between occupied bonding orbitals and unoccupied antibonding orbitals. It is observed in single bonds, double bonds, and transition states. Hyperconjugation explains conformational preferences, reaction rates, and stereochemical outcomes. The anomeric effect, where an axial orientation is favored at anomeric centers, arises from hyperconjugative interactions between the lone pair and antibonding orbital. Substituent effects in SN2 reactions and carbonyl addition reactions can be understood through stabilization of developing partial charges in the transition state by hyperconjugation.

1. Hyperconjugation
Alan B. Northrup
MacMillan Group Meeting
September 17, 2003
Review of the Basics:
Kirby, A.J. "Stereoelectronic Effects," in Oxford Chemistry Primers, New York, 1996, Vol. 36, pp. 3-33.
A semi-quantitative approach to frontier orbital size and application to pericyclic reactions:
Fleming, I. Frontier Orbitals and Organic Chemical Reactions, Wiley; New York, 1998.
Anomeric Effect in Detail:
Kirby, A.J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen, Springer-Verlag; New York, 1983.
Graczyk, P.P.; Mikolajczyk, M. "Anomeric Effect: Origin and Consequences," in Topics in Stereochemistry, 1994, Vol. 21, p 159.
s s*

2. s p
What is Hyperconjugation?
n A Resonance View:
Me
Me
H
H H
H
Me
Me
H H
n Frontier Molecular Orbital Depiction:
H
H
Me
Me
H
HOMO
LUMO
sC-H
p
∆E
Estab
Overlap = S
Estab a
S2
∆E
n Physical Evidence for Hyperconjugation's Existance:
Adamantane
110° 1.530 Å
[SbF5–F–SbF5]–
Adamantyl Cation X-Ray Struture
100.6°
1.431 Å
1.608 Å
Laube, T., et al. Angew. Chem. Int. Ed. 1986, 25, 349

3. s p
Why is Hyperconjugation Stabilizing?
n Remember the H2 Molecule:
n Hyperconjugation Revisited:
H
H
Me
Me
H
HOMO
LUMO
sC-H
p
∆E
Estab
Overlap = S
Estab a
S2
∆E
H1s H1s
H H
distance
Energy
H H
H H
H H
The FMO View:
Stabilization of the highest energy
electrons stabilizes the entire system
One Central Postulate of FMO Theory

4. Conjugation vs. Hyperconjugation
n Butadiene shows a strong preference for planarity
H
H
H
H H
H
H
H
H
∆G = +4 kcal/mol
n Sterics alone cannot account for this large conformational bias
H
H
H
H
p p*
planar non-planar
planar: non-planar:
p p*
no
p
p*
p
p*
Estab a
S2
∆E
n Conjugation and Hyperconjugation are essentialy the same phenomenon
orbitals are orthogonal
MO Diagram:
MO Diagram:

5. Positive, Neutral and Negative Hyperconjugation
n The literature is full of different descriptors for hyperconjugation
Me
Me
H
H H
H
Me
Me
H H
"positive hyperconjugation"
MeO2S
OMe MeO2S
"negative hyperconjugation"
O
N H
Me
Me
O
N H
Me
Me
"neutral hyperconjugation"
n Slight, but significant differences in MO diagrams
s p
H
H
Me
Me
H
HOMO
LUMO
sC-H
p
n p*
HOMO
LUMO
nlp
p*
p
s s*
HOMO
LUMO
nlp-
s*
s
n "Hyperconjugation" will be used to refer to any of the above
OMe

6. Ranking Electron-Donating Ability
n Energies from PES provide a somewhat intuitive order for e- pairs on the same atom:
n C-X bonds, where X is electronegative lower both s and s* orbitals, making them worse donors
R
R
R
> >
H
R
R
R R >
sp3
carbanion sp2
carbanion p-bond
R
R
sp3
-sp3
s-bond
decreasing donating ability
>
R
sp3
-sp2
s-bond
Csp3 Csp3
sC-C
s*C-C
C-C bond: C-F bond:
Csp3
Fsp3
sC-F
s*C-F
Increasing
Donor
Strength
C–C
C–H
C–N
C–O
C–F
n Lone pair energies follow a similar trend
H
P
H
H
H
N
H
H
H
S
H
H
O
H
H Cl
> > > >

7. Ranking Electron-Accepting Ability
n Lower-lying LUMOs are better able to accept electron density
n C-X bonds, where X is electronegative lower both s and s* orbitals, making them better acceptors
>
R R >
sp2
p*
R
R
sp3
-sp3
s*
decreasing accepting ability
>
R
sp3
-sp2
s*
Csp3 Csp3
sC-C
s*C-C
C-C bond: C-F bond:
Csp3
Fsp3
sC-F
s*C-F
Increasing
Acceptor
Strength
C–C
C–H
C–N
C–O
C–F
n A brief note on overlap:
R R
sp p*
>
atomic orbital
s*C-F
s*C-O
s*C-N
s*C-C
s*C-H
syn = = good! anti = = bad!

8. H
H
Conformational Effects of Hyperconjugation: Single Bonds
n Staggered vs. Ecipsed Ethane Conformers
n Conformational Preferences of Esters
H
H
H
H
H
H
H
H
H
H
H
H
Staggered Eclipsed
∆G = +3 kcal/mol
s s*
HOMO
LUMO
sC-H
s*C-H
sC-H
H
H
H
H
Pophristic, V.; Goodman, L. "Hyperconjugation not steric repulsion leads to the staggered structure of ethane." Nature, 2001, 411, 565-568.
See also: Angew. Chem. Int Ed. 2003, 4183-4194 for one paper against and one paper for the above explanation
therefore, each interaction ≈ 1 kcal/mol
n The Gauche Effect
H
Cl
H
O
Me
Example: MOM-Cl
Cl
H
H
O
Me
∆G = +2 kcal/mol
H
O
H
Example: H2O2
H
O
H
n s*C-Cl
H
O
O
Me
H
O
O
Me
∆G = +4.8 kcal/mol
difference: n s*C-O
H
O
O
t-Bu
H
O
O
t-Bu
90:10 syn:anti
difference: n s*C-O
Blom, Gunthard Chem. Phys. Lett. 1981, 84, 267 Oki, M.; Nakanishi, H Bull. Chem. Soc. Jpn. 1970, 43, 2558

9. Structural Effects of Hyperconjugation: Double Bonds
n IR Stretching Frequencies can Indicate the Degree of Hyperconjugation
N
N
D
H3C
N
N
D
H3C
n s*
nlp
s*
s
nN-D = 2317 cm-1
nN-D = 2188 cm-1
nN-N = 1559 cm-1
nN-N = 1565 cm-1
n The Following can be Rationalized with Hyperconjugation
Craig, N. C., et al. J. Am. Chem. Soc. 1979, 101, 2408
1715 cm-1
1745 cm-1
1788 cm-1
1813 cm-1
O O O O
n Position of this Equilibrium Deteremined by an n to s* Hyperconjugative Interaction
O
O
O
O
OMe
O O OMe
>20:1
Vankatataman, H; Cha, J.K. Tet. Lett. 1989, 30, 3509

10. The Anomeric Effect: What is it?
n Anomeric Effect refers to the tendency of anomeric substituens to prefer an axial configuration
OMe
OMe
∆G = –0.6 kcal/mol
O O
OMe
OMe
∆G = +0.6 kcal/mol
n Electron-Withdrawing Groups Increase the Magnitude of the Anomeric Effect
Anomeric Effect is worth ca. 1.2
kcal/mol
O O
Cl
Cl
∆G = +1.8 kcal/mol
Anomeric Effect ≈ 2.8 kcal/mol
O O
X
X
OBz
OBz
BzO
BzO
BzO
BzO
favored for X=F, Cl, Br, OAc
n Hyperconjugation Explains this Effect:
O
O
OMe
OMe
n s*
no overlap possible
axial anomer: equitorial anomer:
nlp
s*
s

11. The Anomeric Effect: Consequences
n Spiroketal Conformations are Controled via the Anomeric Effect
O
O O O O
O >20:1
n Rate of Acetal Hydrolysis can be Impacted Considerably
HO
O
O
H
O
O
O
O
O
O
O
NH
Me
H
H
OH
HO Me
Me
Me
Me
Me
H
H
H
n Azaspiracid Stereochemistry at all 5 Anomeric Centers is Predicted by the Anomeric Effect
O O OAr
H
H
O O OAr
H
H
k1
k2
O O
OH
k2
k1
≈ 200
JCS Chem. Comm. 1979, 1079
O
O
O
O
n s*
k1 slow
k2 fast

12. O
R
The exo-Anomeric Effect
n The exo-Anomeric Effect Concerns the Conformation of an O-Glycosidic Linkage (cf. Gauche Effect)
O
O
R
O
H
n s*
nlp
s*
s
n While Important to Sugar Chemists, only Rarely Exploited in Synthesis:
Gupta, R.C.; Slawin, A.M.Z.; Stoodly, R.J.; Williams, D.J.; J.C.S. Chem. Comm. 1986, 1116.
13% nOe
O
H
OTMS
H
CH2OAc
AcO
AcO
AcO
endo Cycloaddition from Top Face
O
AcOH2C OAc
O
OAc
OAc
OTMS
O
O
O
O
O
O
H
H
OR*
OTMS
8:1 dr

13. H
The Anomeric Effect: It's not just for Oxygen Anymore
n Similar Effects are Noticed with Nitrogen
n Hyperconjugation has Large effects on Even C-H Bonds
n Anomeric Effect in Orthoamides can Cause Strange Reactivity:
N
N
N
t-Bu
t-Bu
t-Bu N
N
N
t-Bu
t-Bu
t-Bu
∆G = –0.35 kcal/mol
Katritzky, A.R. J.C.S. B 1970, 135
N
N
N
Me
Me
Me
Me
Solution Structure (NMR):
Anderson, J. E.; Roberts, J.D. J. Am. Chem. Soc. 1967, 96, 4186
N
N
H10
H6 H4
IR: "Bohlmann Bands"
2700 to 2800 cm-1
for H4, H6, and H10
Disappear when protonated
Bohlmann, Ber. 1958, 91, 2157
1
H NMR: Extra Electron Density Causes Shielding
H10 is furthest upfield
H4 and H6 upfield by almost 1ppm
of remaining protons
Only off by 0.5 ppm when acid is added
N N
N
N
N
N
Illustrated proton d = 2.3 ppm
HBF4
110 °C, 1 day
N N
N
BF4
–
H2
+
Erhardt, J.M; Wuest, J.D. J. Am. Chem. Soc. 1980, 102, 6363

14. The Anomeric Effect: It's not just for Oxygen Anymore
n Dithianes Allow the Study of this Effect for Sulfur
n Carbon is not the only atom through which this effect may be transmitted!
S
S
S
S
R
R
R ∆G (kcal/mol)
SCH3
SPh
CO2Me
COPh
CO2H
NMe2
1.64
2.02
2.10
2.46
>2.65
≈ 0
OMe
BH2Cl•MeS O
B
Me
Cl
H
B-Cl bond = 1.890 Å
X-Ray Structure
lit. range: 1.72-1.877 Å
Shiner, C.S.; Garner, C.M.; Haltiwanger, R.C. J. Am. Chem. Soc. 1985, 107, 7167
n Anomeric Effect Through Phosphorous can be Significant for Phosphite Reactiviy
(EtO)3P: + 2 EtOSPh
pentane
–78 °C
P(OEt)5 + PhSSPh
O
P
O
O + 2 EtOSPh
r.t.
N.R.
P(OEt)5
OH
OH
OH O
P
O
O
OEt
OEt
O
P
O
O
no donation possible
OEt
SPh

15. The Role of Hyperconjugation in the Transition State: Theory
n The SN2 Reaction TS looks like a 3c-4e–
Bond:
H
H H
Br
I
I–
CH3Br
+ I CH3
n MO Diagram for a 3c-4e–
Bond:
2
1
Basis Set:
bonding
nonbonding
antibonding
Prediction: Substituents with Low-Lying LUMOs will Accelerate the Sn2 by Stabilizing
Electron Density from Nucleophile and Leaving Group through Hyperconjugation
Theoretical Support for the following Arguments: Houk, K. N., et al. Science, 1986, 231, 1109

16. Transition State Hyperconjugation Explains Substituent Effects in the SN2 Reaction
n Here's the Rate Data on the SN2 Reaction:
I– + R Cl
Acetone
I R
Entry R krel a-LUMO
1
2
3
4
5
6
7
n-Bu
cylcohexyl
PhCO2CH2
Allyl
Benzyl
NCCH2
PhCOCH2
1.0
<0.0001
59.1
79
195
3,070
105,000
s*C-C
s*C-C
s*C-O
p*C-C
p*C-C
p*C-N
p*C-O
sterics are still important
n Data fits the Following Model
Conant, J.B.; Kinner, W.R.; Hussey, R.E. J. Am. Chem. Soc. 1925, 47, 488
Cl
I–
TS HOMO
p*
p

17. Hyperconjugation in Carbonyl Addition Reactions
n The Carbonyl Addition Reaction
n Origin of Diastereoselectivity Subject of Much Debate (See NAP Group Meeting)
H
H
O
Nu
p*
O
H
H
Nu
Nu
HO H
H
Felkin Model Predicts Ketones Well, Fails for Aldehydes:
RL
H RM
O
R
RL
H RM
R
O
Nu
destabilizing
interaction
R
O
RL
RM
Nu
R
RL
RM
Nu OH
Nu
favored disfavored
H
O
RL
RM
Nu
H
RL
RM
Nu OH
RL
H RM
O
H
RL
H RM
H
O
Nu
destabilizing
interaction
Nu
favored
disfavored
predicts
wrong
product!
Ahn and Eisenstein add the Dunitz-Burgi Trajectory and the "Antiperiplanar Effect":
RL
H RM
O
R
RL
H RM
R
O
Nu
destabilizing
interaction
Nu
favored disfavored
rationalized stereochemistry
for aldehydes and ketones

18. The "Antiperiplanar Effect":Hyperconjugation in Action
n Polar Substituents act as RL in the Felkin-Ahn Model:
n Transition State Hyperconjugation, or How SMe can act Larger than i-Pr
TS HOMO
s*C-R
sC-R
Me
Me
SMe
O
Ph
LiBH(s-Bu)3
Me
Me
SMe
OH
Ph
Me
Me
SMe
OH
Ph
96:4 syn:anti
Shimagaki Tet. Lett. 1984, 25, 4775
RL
H RM
O
R
Nu
favored
SMe
H i-Pr
O
R
favored
H–
RL
H RM
O
R
nNu
p*C-O
s*C-R L
Predicts Better Acceptor at RL
leads to better selectivity
n Sterics Predicts the Opposite Trend:
R
H
O
Me
Me
Me
OLi
OMe
R
OH
Me Me Me
OMe
O
R= c-C6H11 9:1 syn:anti
R= Ph >200:1 syn:anti

19. H
Transition State Hyperconjugation in C=O Additions: Cieplak
n A Much Maligned Theory:
n Cieplak: Transition State is stabilized by an interaction between a filled substrate orbital and TS s* orbital
"Structures are stabilized by stabilizing their highest energy filled states. This is one of the fundamental
assumptions in frontier molecular orbital theory. The Cieplak hypothesis is nonsense."
—Prof. David A. Evans
Chem 206 Lecture Notes
s*TS
R
H R
O
R
s*TS
sC-R
sC-R
Cieplak, A.S. J. Am. Chem. Soc. 1981, 103, 4540
n Cieplak and Felkin-Ahn Both Usually Predict Same Sense of Diastereoselection
t-Bu
O
H
s*C-H
sTS
Felkin-Ahn: Axial Attack Favored
t-Bu
O
s*C-C
sTS
t-Bu
O
sC-H
s*TS
Cieplak: Axial Attack Favored
t-Bu
O
sC-C
s*TS
favored disfavored
favored disfavored

20. Transition State Hyperconjugation in C=O Additions: Cieplak
n Examples consistent with Cieplak but not Felkin-Ahn
n le Noble Has Many Examples with 2-Adamantanones:
O
R
R
Nu
R
R
R
R
HO Nu Nu OH
R=EWG, Shaded bond's s*, better acceptor, F-A predicts anti
syn anti
R=EWG, Shaded bond's, worse donor, Cieplak predicts syn
R Nu syn:anti
CO2Me
CH2OMe
CH2=CH2
Et
LAH
MeLi
NaBH4
MeLi
LAH
MeLi
NaBH4
MeLi
87:13
>90:10
40:60
34:66
35:65
27:73
20:80
17:83
Chem. Rev. 1999, 99, 1387-1467
O
R
Nu
R R
HO Nu Nu OH
syn anti
Same argument as above
R Nu syn:anti
CO2Me
F
TMS
SnMe3
NaBH4
MeLi
NaBH4
MeLi
NaBH4
MeLi
NaBH4
MeLi
57:43
55:45
62:38
70:30
50:50
49:51
48:52
48:52

21. Breakdown of the Cieplak Model: Is it Simply Electrostatics?
n Critics of Cieplak Cite Role of Electrostatics in pro-Cieplak Examples:
n Die-Hard Proponents of Cieplak Have a Hard Time Explaining This Houk Example:
O
CO2Me
CO2Me
Nu
d
d+
+
is syn product due to
simple electrostatic attraction?
O
Et
Et
Nu
d
d-
-
is anti product due to
simple electrostatic repulsion?
O
EWG
O
EWG
Cieplak Prediction: Equatorial EWG should lower shaded bonds' donor strength, leading to more axial attack for A than B
A B
Diastereomer EWG axial:eq.
N.A.
A
B
A
B
H
OAc
OAc
Cl
Cl
60:40
71:29
83:17
71:29
88:12
n Houk Invokes an Electrostatic Argument to Explain B's Enhanced axial selectivity
Houk, K.N., et al. J. Am. Chem. Soc. 1991, 113, 5018
O
EWG
d+
Nu
Axial Approach Trajectory
O
EWG
Equitorial Approach Trajectory
d- Nu
unfavorable
favorable

22. The b-Silicon Effect: Hyperconjugation Yet Again
n A Silicon b to a Leaving Group Greatly Enhances Ionization
n Late Transition State for Rate-Determining Ionization (Endothermic)
t-Bu
OTFA
X
solvent
t-Bu
X
TFA
t-Bu TFA–X
kSi
kH
= 2.4 x 1012
bridged intermediates ruled out
by Deuterium isotope effects
Lambert et al. Acc. Chem. Res. 1999, 32, 183
Rxn Coordinate
Energy
TS
sm
cation
t-Bu
SiR3
hyperconjugation
stabilizes cation
sC-Si
p
n Why is C-Si so much better a donor than C-H? Look at the bonds!
Csp3
Sisp3
BDE ≈ 72 kcal/mol
Csp3
H1s
BDE ≈ 102 kcal/mol
C–H
good overlap
C–Si
worse overlap
C–Si bond has a much higher HOMO

23. Nucleophillic Olefin Addition Reactions: Homo-Raising Hyperconjugation
n Nucleophillic olefins constitute a key class of reagents
n Hyperconjugation Raises the p HOMO of the alkene by donation to the p*
H
Me
Me
OH
O
TMS
O
H
Me
BL2 O
H
Me
NMe2
Me
O
H
Me
O
Me
O
H
Me
H
O
H
Me
Me
O
Me
O
C
" "
H
s or n p*
s or n
p*
p
N.B.: The p orbital is raised in energy
Magnitude of HOMO-raising is
related to amount of donation
to the p*

24. Enamines: A Case Study in Hyperconjugation
n Like amides there is restricted rotation about the C-N bond
n E-Enamines prefer a near Gauche-Out conformation While Z-Enamines prefer Orthogonal In
-90 -60 -30 0 30 60 90
Lone Pair Torsion Angle
Relative
Energy
(kcal/mol)
N,N-Dimethylvinylamine
(E)-1-Dimethylaminopropene
(Z)-1-Dimethylaminopropene
0
2
4
6
8
Me
N Me
0°
+90°
Weston, J.W.; Albrecht, H. J.C.S. Perkin 2, 1997, 1003
q
Me2N Me2N
Me
Me2N Me
"orthoganol in"
"gauche out"
"orthogonal out"
"gauche in"
Me
N Me
R
N
R
Me
Me
N
R
Gauche Out
Me
Me
Orthogonal Out
Orthogonal In Gauche In
N
R
Me
Me
align electron-density on N with p-bond
align electron-density on N with p*

25. Consequences of Enamine Conformation on Reactivity
n Hyperconjugation not only stabilizes "gauche out" but also makes it more reactive:
n Following MO Diagrams Illustrate the Difference
sC-N
p*
p
Me
N Me
gauche out
Me2N
Me
1
2
13
C NMR:
C1: 127.4 ppm
C2: 86.3 ppm
1
H NMR:
H1: 5.76 ppm
H2: 4.10 ppm
∆d = 1.66 ppm
∆d = 41.1 ppm
Me
Me
N Me
Me2N Me
1 2
13
C NMR:
C1: 132.1 ppm
C2: 93.4 ppm
1
H NMR:
H1: 5.30 ppm
H2: 4.30 ppm
∆d = 1.00 ppm
∆d = 38.7 ppm
Lambert, J.B. et al. J. Am. Chem. Soc. 1980, 102, 6659
orthogonal in
Orthogonal In: 2 sC-N to p*:
nN
p*
p
Gauche Out: 1 nN to p* and 1 sC-N to p*
More hyperconjugation, higher p HOMO
alkene more reactive
Less hyperconjugation, lower p HOMO
alkene less reactive

26. Mechanism of Enamine Hydrolysis: Implications for Aldol Chemistry
n Two Competing Ideas for Enamine Hydrolysis
N
Me Me
H+
H+
N
Me Me
N
Me Me
H
C-protonation
H
N-protonation
intermol.
H+
transfer
N
Me Me
H
as above O
Me
N
Me Me
H
HO
O
Me
+ NHMe2
+ NHMe2
n Hyperconjugation makes N protonation difficult
Me Me
N
Me 1:1 AcOH:NaOAc pH=5
Me Me
N
Me
–
OAc 80 °C
Me Me
N
–
OAc
Me
C-protonation
equilibration
Me Me
N
Me 12N HCl or 12N HClO4
Me Me
N
Me
H
X–
9:1 d.r.
5h
1:4 d.r.
stable
rt or 80 °C
N-protonation
Bathélémy, M.; Bessiere, Y. Tetrahedron 1976, 32, 1665

27. Enamines in the Aldol Reaction: Computational Considerations
n The Enamine Aldol Rection
n Computed Properties of the Transition State
NMe2 O
H Me
H+
N
Me Me
H2O
H
O
H Me
Me
A surprisingly late transition state:
O OH
"Normal" Bond Lengths
C–C 1.544 Å
C–N 1.492 Å
C–O 1.470 Å
n What a Late Transition State Means for the Aldol
O
N
Me
Me
…not this!
O
N
Me
Me
TS looks more like this…
n Protonation only increases product devel in TS
n Non-basic enamine N in TS (Hyperconjugation)
n C-N Conformation locked in "gauche out"

28. Proline-Catalyzed Aldol Rection Transition States
n The Direct Aldehyde-Aldehyde Aldol Reaction
H
O
Me
H
O
Me
10 mol% L-Proline
DMF, +4 °C
O
H
Me
Me
OH 80% yield
4:1 anti:syn
99% ee (anti)
n Barbas-List Transition State
H
N
O O
O
Me
Et
H
n Jorgenson's Transition State
H
N
O O
O
Me
Et
H
n MacMillan's Transition State
H
N
O O
O
Me
Et
H
n First Model
n Correctly Predicts Stereochemistry
n Bifurcated H-bond
n Rigid 5-6 system
n Intimate Involvement of Chirality
n Second Model
n Correctly Predicts Stereochemistry
n Removes Bifurcated H-bond
n 9-membered Ring (8 planar centers)
n Intimate Involvement of Chirality
n Third Model
n Correctly Predicts Stereochemistry
n Removes Bifurcated H-bond
n Rigid 6 membered system
n No Intimate Involvement of Chirality
n Disregards Hyperconjugation
n Imporves Hyperconjugation

29. Hyperconjugation Conclusions
n s* s s*
n p* s p*
It's a simple, but powerful theory.