Hyperconjugation

s s*

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.
 What is Hyperconjugation?

n A Resonance View:
H H
Me Me
Me Me
H H H H

n Frontier Molecular Orbital Depiction:

Overlap = S
H p
HOMO S2
Me Estab a
∆E
∆E
H Me
H LUMO
sC-H
s p
Estab

n Physical Evidence for Hyperconjugation's Existance:

1.431 Å
[SbF5–F–SbF5]–

100.6° 1.608 Å
110° 1.530 Å

Adamantyl Cation X-Ray Struture

Adamantane
Laube, T., et al. Angew. Chem. Int. Ed. 1986, 25, 349
 Why is Hyperconjugation Stabilizing?
n Remember the H2 Molecule:
One Central Postulate of FMO Theory
Stabilization of the highest energy
HH
electrons stabilizes the entire system

distance
The FMO View:
H H
Energy

H H

H1s H1s

H H

n Hyperconjugation Revisited:

Overlap = S
H p
HOMO S2
Me Estab a
∆E
∆E
H Me
H LUMO
sC-H
s p
Estab
 Conjugation vs. Hyperconjugation

n Butadiene shows a strong preference for planarity

H H
H H
H ∆G = +4 kcal/mol
H H
H
H
planar non-planar
n Sterics alone cannot account for this large conformational bias

planar: non-planar:

H H
H H orbitals are orthogonal

p p*
no p p*
MO Diagram:
MO Diagram:

p*
p*

p S2
p
Estab a
∆E

n Conjugation and Hyperconjugation are essentialy the same phenomenon

 Positive, Neutral and Negative Hyperconjugation
n The literature is full of different descriptors for hyperconjugation

H H O O
OMe
Me Me Me Me OMe
MeO2S MeO2S
Me Me N H N H
H H H H
Me Me

"positive hyperconjugation" "neutral hyperconjugation" "negative hyperconjugation"

n Slight, but significant differences in MO diagrams

LUMO
H
HOMO HOMO
HOMO
Me
H Me LUMO
H LUMO n p* s s*
s p

p s*
p*
nlp-
nlp

sC-H
p
s
n "Hyperconjugation" will be used to refer to any of the above
 Ranking Electron-Donating Ability
n Energies from PES provide a somewhat intuitive order for e- pairs on the same atom:

R R
R R > > > >
R R R
R H
R R
sp3 carbanion sp2 carbanion p-bond sp3-sp3 s-bond sp3-sp2 s-bond

decreasing donating ability

n C-X bonds, where X is electronegative lower both s and s* orbitals, making them worse donors

C-C bond: C-F bond:

s*C-C C–C

Increasing Donor Strength

s*C-F
C–H

Csp3 Csp3 Csp3 C–N

Fsp3 C–O

sC-C
sC-F C–F

n Lone pair energies follow a similar trend

H H H H
H P > S > H N > O > H Cl
H H H H
 Ranking Electron-Accepting Ability
n Lower-lying LUMOs are better able to accept electron density
R
> R R > > >
R R
R R
atomic orbital sp p* 2
sp p* sp3-sp2 s* 3 3
sp -sp s*

decreasing accepting ability

n C-X bonds, where X is electronegative lower both s and s* orbitals, making them better acceptors

C-C bond: C-F bond:

Increasing Acceptor Strength

s*C-C C–F s*C-F
s*C-F
C–O s*C-O

Csp3 Csp3 Csp3 C–N s*C-N

Fsp3 C–C s*C-C

sC-C s*C-H
sC-F C–H

n A brief note on overlap:

syn = = good! anti = = bad!

 Conformational Effects of Hyperconjugation: Single Bonds
n Staggered vs. Ecipsed Ethane Conformers

H
s*C-H
H HH HOMO H
H H H
H sC-H
H H H H
H H H
H LUMO
Staggered Eclipsed H
s s*
∆G = +3 kcal/mol
therefore, each interaction ≈ 1 kcal/mol

Pophristic, V.; Goodman, L. "Hyperconjugation not steric repulsion leads to the staggered structure of ethane." Nature, 2001, 411, 565-568. sC-H
See also: Angew. Chem. Int Ed. 2003, 4183-4194 for one paper against and one paper for the above explanation

n The Gauche Effect

Example: MOM-Cl Example: H2O2

Cl H H
Me Me H H
O O O O
H H Cl H H

n s*C-Cl ∆G = +2 kcal/mol

n Conformational Preferences of Esters

O O O O

Me ∆G = +4.8 kcal/mol t-Bu 90:10 syn:anti

H O H O H O H O
Me t-Bu
difference: n s*C-O difference: n s*C-O

Blom, Gunthard Chem. Phys. Lett. 1981, 84, 267 Oki, M.; Nakanishi, H Bull. Chem. Soc. Jpn. 1970, 43, 2558
 Structural Effects of Hyperconjugation: Double Bonds
n IR Stretching Frequencies can Indicate the Degree of Hyperconjugation

n s*
D
N N s*
N N
H3C H3C D
nlp
nN-D = 2317 cm-1 nN-D = 2188 cm-1
nN-N = 1559 cm-1 nN-N = 1565 cm-1

Craig, N. C., et al. J. Am. Chem. Soc. 1979, 101, 2408

s
n The Following can be Rationalized with Hyperconjugation

O O O O

1715 cm-1 1745 cm-1 1788 cm-1 1813 cm-1

n Position of this Equilibrium Deteremined by an n to s* Hyperconjugative Interaction

O O

>20:1

O O OMe O O OMe

Vankatataman, H; Cha, J.K. Tet. Lett. 1989, 30, 3509

 The Anomeric Effect: What is it?
n Anomeric Effect refers to the tendency of anomeric substituens to prefer an axial configuration

OMe
O O
OMe OMe

OMe
∆G = –0.6 kcal/mol ∆G = +0.6 kcal/mol Anomeric Effect is worth ca. 1.2
kcal/mol

n Electron-Withdrawing Groups Increase the Magnitude of the Anomeric Effect

BzO
O O OBz
Cl O O
BzO
BzO X
Cl
BzO
OBz X
∆G = +1.8 kcal/mol
Anomeric Effect ≈ 2.8 kcal/mol favored for X=F, Cl, Br, OAc

n Hyperconjugation Explains this Effect:

axial anomer: equitorial anomer:

s*
O nlp
O
OMe
OMe

no overlap possible
n s*

s
 The Anomeric Effect: Consequences
n Spiroketal Conformations are Controled via the Anomeric Effect

O
O O O O

O >20:1

n Azaspiracid Stereochemistry at all 5 Anomeric Centers is Predicted by the Anomeric Effect

O
H
HO O
H
O O OH
H
Me O
H HO Me
O
NH H
Me
O
O
O Me
Me H
Me
n Rate of Acetal Hydrolysis can be Impacted Considerably
H O
O O OAr k1 O k1 slow

O OH O
H

H
O O OAr O
k2 k2 fast
k2 O
≈ 200
H k1
JCS Chem. Comm. 1979, 1079 n s*
 The exo-Anomeric Effect
n The exo-Anomeric Effect Concerns the Conformation of an O-Glycosidic Linkage (cf. Gauche Effect)

n s*
s*

O O nlp
R
H
O
R

s
n While Important to Sugar Chemists, only Rarely Exploited in Synthesis:

O OTMS
OTMS O CH2OAc
H
O OTMS AcO O
OAc O
O
O H
AcO H
H O
AcOH2C OAc O O OR* AcO 13% nOe
OAc
8:1 dr
endo Cycloaddition from Top Face

Gupta, R.C.; Slawin, A.M.Z.; Stoodly, R.J.; Williams, D.J.; J.C.S. Chem. Comm. 1986, 1116.
 The Anomeric Effect: It's not just for Oxygen Anymore
n Similar Effects are Noticed with Nitrogen
Katritzky, A.R. J.C.S. B 1970, 135 Solution Structure (NMR):
t-Bu Me
t-Bu N N t-Bu N N
N t-Bu
N Me N N
N N Me
t-Bu t-Bu
Me
∆G = –0.35 kcal/mol
Anderson, J. E.; Roberts, J.D. J. Am. Chem. Soc. 1967, 96, 4186
n Hyperconjugation has Large effects on Even C-H Bonds
IR: "Bohlmann Bands" 1
H NMR: Extra Electron Density Causes Shielding
2700 to 2800 cm -1 H10
H6 H4
for H4, H6, and H10 H10 is furthest upfield
N
Disappear when protonated H4 and H6 upfield by almost 1ppm
of remaining protons
Bohlmann, Ber. 1958, 91, 2157
Only off by 0.5 ppm when acid is added
n Anomeric Effect in Orthoamides can Cause Strange Reactivity:

N
N HBF4 BF4–
N N N N
N N + H2
H 110 °C, 1 day
N

Illustrated proton d = 2.3 ppm

Erhardt, J.M; Wuest, J.D. J. Am. Chem. Soc. 1980, 102, 6363
 The Anomeric Effect: It's not just for Oxygen Anymore
n Dithianes Allow the Study of this Effect for Sulfur
R ∆G (kcal/mol)

SCH3 1.64
R
SPh 2.02
S CO2Me 2.10
S R
S S
COPh 2.46
CO2H >2.65
NMe2 ≈0

n Carbon is not the only atom through which this effect may be transmitted!

BH2Cl•MeS O B-Cl bond = 1.890 Å

MeH
OMe B lit. range: 1.72-1.877 Å
Cl

X-Ray Structure
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

pentane
(EtO)3P: + 2 EtOSPh P(OEt)5 + PhSSPh SPh
–78 °C
OEt
O r.t.
+ N.R. P
O P 2 EtOSPh O O
O
O

OH O OEt
O P
P(OEt)5 OH OEt
O no donation possible
OH
 The Role of Hyperconjugation in the Transition State: Theory
n The SN2 Reaction TS looks like a 3c-4e– Bond:

H
– +
I CH3Br I CH3
I Br
H H

n MO Diagram for a 3c-4e– Bond:

antibonding
Basis Set:

2 nonbonding

1
bonding

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
 Transition State Hyperconjugation Explains Substituent Effects in the SN2 Reaction
n Here's the Rate Data on the SN2 Reaction:

Acetone
I– + R Cl I R

Entry R krel a-LUMO

1 n-Bu 1.0 s*C-C

2 cylcohexyl <0.0001 s*C-C sterics are still important

3 PhCO2CH2 59.1 s*C-O

4 Allyl 79 p*C-C
5 Benzyl 195 p*C-C
6 NCCH2 3,070 p*C-N
7 PhCOCH2 105,000 p*C-O

Conant, J.B.; Kinner, W.R.; Hussey, R.E. J. Am. Chem. Soc. 1925, 47, 488

n Data fits the Following Model

I–
p*

TS HOMO
Cl

p
 Hyperconjugation in Carbonyl Addition Reactions
n The Carbonyl Addition Reaction
Nu Nu
Nu
H
H O H
O H HO
H H
p*

n Origin of Diastereoselectivity Subject of Much Debate (See NAP Group Meeting)

Felkin Model Predicts Ketones Well, Fails for Aldehydes:

O O
Nu Nu OH Nu Nu OH
RM RM RM RM
R R H H
RL RL RL RL
Nu Nu Nu Nu

H RM H RM H RM predicts
R O O R H O H RM
destabilizing O H wrong
RL RL destabilizing product!
interaction RL
interaction RL
favored disfavored disfavored favored
Ahn and Eisenstein add the Dunitz-Burgi Trajectory and the "Antiperiplanar Effect":

Nu
Nu
H RM H RM destabilizing rationalized stereochemistry
R O O R interaction for aldehydes and ketones
RL RL
favored disfavored
 The "Antiperiplanar Effect":Hyperconjugation in Action
n Polar Substituents act as RL in the Felkin-Ahn Model:

Me O Me OH Me OH Nu H–
LiBH(s-Bu)3
H RM H i-Pr
Me Ph Me Ph Me Ph R O R O
SMe SMe SMe RL SMe
favored favored
96:4 syn:anti

Shimagaki Tet. Lett. 1984, 25, 4775

n Transition State Hyperconjugation, or How SMe can act Larger than i-Pr

s*C-R
nNu s*C-R L
Predicts Better Acceptor at RL
H RM leads to better selectivity
R O
TS HOMO

p*C-O
RL

sC-R
n Sterics Predicts the Opposite Trend:
OLi
Me
O OMe OH O
R= c-C6H11 9:1 syn:anti
R Me R
H OMe R= Ph >200:1 syn:anti
Me
Me Me Me
 Transition State Hyperconjugation in C=O Additions: Cieplak

n Cieplak: Transition State is stabilized by an interaction between a filled substrate orbital and TS s* orbital

s*TS

s*TS
H R
R O
sC-R
sC-R R

Cieplak, A.S. J. Am. Chem. Soc. 1981, 103, 4540

n Cieplak and Felkin-Ahn Both Usually Predict Same Sense of Diastereoselection

Felkin-Ahn: Axial Attack Favored Cieplak: Axial Attack Favored

sTS s*TS s*TS

s*C-H O s*C-C O O O
t-Bu t-Bu sTS t-Bu t-Bu
H sC-C
H sC-H
favored disfavored disfavored
favored
n A Much Maligned Theory:
"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
 Transition State Hyperconjugation in C=O Additions: Cieplak
n Examples consistent with Cieplak but not Felkin-Ahn

O R Nu syn:anti
HO Nu Nu OH
CO2Me LAH 87:13
Nu MeLi >90:10

R R R CH2OMe NaBH4 40:60

R R R MeLi 34:66
syn anti
CH2=CH2 LAH 35:65
R=EWG, Shaded bond's s*, better acceptor, F-A predicts anti MeLi 27:73
R=EWG, Shaded bond's, worse donor, Cieplak predicts syn Et NaBH4 20:80
MeLi 17:83

Chem. Rev. 1999, 99, 1387-1467

n le Noble Has Many Examples with 2-Adamantanones:

R Nu syn:anti
CO2Me NaBH4 57:43
O MeLi 55:45
HO Nu Nu OH
Nu F NaBH4 62:38
MeLi 70:30

TMS NaBH4 50:50

R R R
MeLi 49:51
syn anti
SnMe3 NaBH4 48:52
Same argument as above MeLi 48:52
 Breakdown of the Cieplak Model: Is it Simply Electrostatics?
n Critics of Cieplak Cite Role of Electrostatics in pro-Cieplak Examples:
O O
Nu
d+
Nu d-
d+ d-
CO2Me Et
CO2Me Et

is syn product due to is anti product due to

simple electrostatic attraction? simple electrostatic repulsion?

n Die-Hard Proponents of Cieplak Have a Hard Time Explaining This Houk Example:
Cieplak Prediction: Equatorial EWG should lower shaded bonds' donor strength, leading to more axial attack for A than B

Diastereomer EWG axial:eq.

O O N.A. H 60:40
EWG A OAc 71:29
B OAc 83:17
A EWG
B
A Cl 71:29
B Cl 88:12
Houk, K.N., et al. J. Am. Chem. Soc. 1991, 113, 5018

n Houk Invokes an Electrostatic Argument to Explain B's Enhanced axial selectivity

Equitorial Approach Trajectory Axial Approach Trajectory
O
Nu
O
favorable
EWG d - Nu
d+

unfavorable EWG
 The b-Silicon Effect: Hyperconjugation Yet Again
n A Silicon b to a Leaving Group Greatly Enhances Ionization
X X
solvent
t-Bu t-Bu t-Bu TFA–X

OTFA
TFA
kSi
12
= 2.4 x 10 bridged intermediates ruled out
kH by Deuterium isotope effects

Lambert et al. Acc. Chem. Res. 1999, 32, 183

n Late Transition State for Rate-Determining Ionization (Endothermic)

TS

cation SiR3
Energy

p
t-Bu
sC-Si

hyperconjugation
sm stabilizes cation
Rxn Coordinate
n Why is C-Si so much better a donor than C-H? Look at the bonds!

C–H C–Si

good overlap worse overlap Sisp3

H1s
Csp3 Csp3 BDE ≈ 72 kcal/mol

BDE ≈ 102 kcal/mol

C–Si bond has a much higher HOMO
 Nucleophillic Olefin Addition Reactions: Homo-Raising Hyperconjugation
n Nucleophillic olefins constitute a key class of reagents

NMe2 TMS
O O
Me Me
H H
Me

O OH
O O BL2 O
Me
Me H Me
H H
Me
Me

O H
" O " O
Me Me
C
H
H Me

n Hyperconjugation Raises the p HOMO of the alkene by donation to the p*

p*

s or n
N.B.: The p orbital is raised in energy
s or n p* Magnitude of HOMO-raising is
related to amount of donation
to the p*
p
 Enamines: A Case Study in Hyperconjugation
n Like amides there is restricted rotation about the C-N bond

8
Me2N Me2N Me2N Me

Relative Energy (kcal/mol)

Me 6 N,N-Dimethylvinylamine
(E)-1-Dimethylaminopropene
0° (Z)-1-Dimethylaminopropene

q
4

+90° N Me
0
-90 -60 -30 0 30 60 90
Me
"orthoganol in" Lone Pair Torsion Angle "orthogonal out"
Weston, J.W.; Albrecht, H. J.C.S. Perkin 2, 1997, 1003
"gauche in" "gauche out"

n E-Enamines prefer a near Gauche-Out conformation While Z-Enamines prefer Orthogonal In

Me Me

N Me N N Me N
R R R R
Me Me
Me Me
Gauche Out Orthogonal In Orthogonal Out Gauche In

align electron-density on N with p* align electron-density on N with p-bond

 Consequences of Enamine Conformation on Reactivity
n Hyperconjugation not only stabilizes "gauche out" but also makes it more reactive:

Me2N Me Me2N Me
2
1 N 1 2
Me Me
N Me
13 1 13 1
C NMR: H NMR: Me C NMR: H NMR:
Me C1: 127.4 ppm H1: 5.76 ppm C1: 132.1 ppm H1: 5.30 ppm
C2: 86.3 ppm H2: 4.10 ppm orthogonal in C2: 93.4 ppm H2: 4.30 ppm
gauche out ∆d = 41.1 ppm ∆d = 1.66 ppm ∆d = 38.7 ppm ∆d = 1.00 ppm
Lambert, J.B. et al. J. Am. Chem. Soc. 1980, 102, 6659

n Following MO Diagrams Illustrate the Difference

Gauche Out: 1 nN to p* and 1 sC-N to p*

p* p*
More hyperconjugation, higher p HOMO
alkene more reactive nN

sC-N
Orthogonal In: 2 sC-N to p*:

Less hyperconjugation, lower p HOMO

alkene less reactive p p
 Mechanism of Enamine Hydrolysis: Implications for Aldol Chemistry
n Two Competing Ideas for Enamine Hydrolysis
Me Me Me Me O
N N
+ + NHMe2
H
H H Me
HO
Me Me
N C-protonation

H
H + Me Me intermol. Me Me as above O
N N + NHMe2
+
H transfer H Me

N-protonation
n Hyperconjugation makes N protonation difficult

Me Me Me MeMe Me Me
Me 1:1 AcOH:NaOAc pH=5 –
OAc –
OAc
80 °C Me
N 5h N N
equilibration
C-protonation
9:1 d.r. 1:4 d.r.

Me Me Me Me
Me 12N HCl or 12N HClO4 Me X–

N rt or 80 °C N
H
N-protonation
stable

Bathélémy, M.; Bessiere, Y. Tetrahedron 1976, 32, 1665

 Enamines in the Aldol Reaction: Computational Considerations
n The Enamine Aldol Rection

Me Me
NMe2 O H+ N O H2O O OH

H Me H Me H Me

n Computed Properties of the Transition State

A surprisingly late transition state:

"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

Me Me n Protonation only increases product devel in TS

N N
OMe OMe n Non-basic enamine N in TS (Hyperconjugation)

n C-N Conformation locked in "gauche out"

TS looks more like this… …not this!
 Proline-Catalyzed Aldol Rection Transition States
n The Direct Aldehyde-Aldehyde Aldol Reaction

O O O OH 80% yield
10 mol% L-Proline
Me 4:1 anti:syn
H H H
DMF, +4 °C
Me Me Me 99% ee (anti)

n Barbas-List Transition State n Jorgenson's Transition State n MacMillan's Transition State

N N N
Me Me Me
Et O Et O Et O
H H H

O O O O O O
H H H

n First Model n Second Model n Third Model

n Correctly Predicts Stereochemistry n Correctly Predicts Stereochemistry n Correctly Predicts Stereochemistry

n Bifurcated H-bond n Removes Bifurcated H-bond n Removes Bifurcated H-bond

n Rigid 5-6 system n 9-membered Ring (8 planar centers) n Rigid 6 membered system

n Intimate Involvement of Chirality n Intimate Involvement of Chirality n No Intimate Involvement of Chirality

n Imporves Hyperconjugation n Disregards Hyperconjugation

 Hyperconjugation Conclusions

It's a simple, but powerful theory.

n s* n p* s s* s p*