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 H Me Me H H H Me Me

n Frontier Molecular Orbital Depiction:

Overlap = S
H

p
Me

HOMO E Estab
a

S2 E

H H

Me

LUMO

sC-H
Estab

n Physical Evidence for Hyperconjugation's Existance:

1.431 [SbF5FSbF5] 100.6 1.608

110

1.530

Adamantane

Adamantyl Cation X-Ray Struture

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

Why is Hyperconjugation Stabilizing?

n Remember the H2 Molecule:
HH One Central Postulate of FMO Theory

Stabilization of the highest energy electrons stabilizes the entire system

distance

The FMO View: H H

Energy

H H1s H1s

n Hyperconjugation Revisited:
Overlap = S
H

p
Me

HOMO E Estab
a

S2 E

H H

Me

LUMO

sC-H
Estab

Conjugation vs. Hyperconjugation

n Butadiene shows a strong preference for planarity
H H H H H H H H

G = +4 kcal/mol
H

planar

non-planar

n Sterics alone cannot account for this large conformational bias

planar:
H H H H

non-planar:

orbitals are orthogonal

p
MO Diagram:

p*
no MO Diagram:

p*

p*

p*

Estab

S2 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 H Me Me H H H Me Me Me N Me O H Me N Me O H MeO2S OMe MeO2S

OMe

"positive hyperconjugation"

"neutral hyperconjugation"

"negative hyperconjugation"

n Slight, but significant differences in MO diagrams

H

LUMO HOMO
Me

HOMO
H H Me

HOMO

LUMO

p*

s*

LUMO

p* nlpnlp

s*

sC-H p n "Hyperconjugation" will be used to refer to any of the above s

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 H

> sp2 carbanion

R R R

>
R

>
R

sp3 carbanion

p-bond decreasing donating ability

sp3-sp3 s-bond

sp3-sp2 s-bond

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

s*C-F
Csp3 Csp3 Csp3 Fsp3

Increasing Donor Strength

s*C-C

C-F bond: CC CH CN CO CF

sC-C n Lone pair energies follow a similar trend

H H P H H H S H

sC-F

>

>

N H

>
H

>

Cl

Ranking Electron-Accepting Ability

n Lower-lying LUMOs are better able to accept electron density
> atomic orbital
R R R R R

>

>
R

>
R

sp p*

sp p* decreasing accepting ability

sp3-sp2 s*

sp -sp s*

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

C-C bond:

s*C-C

C-F bond:

CF CO CN CC CH

s*C-F s*C-O s*C-N s*C-C s*C-H

s*C-F
Csp3 Csp3 Csp3 Fsp3

sC-C n A brief note on overlap:

sC-F

syn =

= good!

anti =

= bad!

Conformational Effects of Hyperconjugation: Single Bonds

n Staggered vs. Ecipsed Ethane Conformers
H
H H H H H HH H H H H

HOMO
H H

H H

s*C-H sC-H

LUMO

Staggered

Eclipsed

G = +3 kcal/mol therefore, each interaction 1 kcal/mol

s*

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

sC-H

n The Gauche Effect

Example: MOM-Cl
Cl H O Me H Cl H O Me H

Example: H2O2
H O H H H

s*C-Cl

G = +2 kcal/mol

n Conformational Preferences of Esters

O H O Me H O O Me O O O

G = +4.8 kcal/mol

t-Bu

90:10 syn:anti

difference: n

s*C-O
Blom, Gunthard Chem. Phys. Lett. 1981, 84, 267

difference: n

s*C-O

t-Bu

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
D N H3C N H3C N N D

s* s* nlp

nN-D = 2317 cm-1 nN-N = 1559 cm-1

nN-D = 2188 cm-1 nN-N = 1565 cm-1

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

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 OMe O OMe O 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

O Cl O Cl BzO OBz O BzO BzO BzO O X

G = +1.8 kcal/mol Anomeric Effect 2.8 kcal/mol

OBz

favored for X=F, Cl, Br, OAc

n Hyperconjugation Explains this Effect:

axial anomer: equitorial anomer:

s*
O OMe O OMe

nlp

no overlap possible n

s* s

The Anomeric Effect: Consequences

n Spiroketal Conformations are Controled via the Anomeric Effect
O O

O O

>20:1

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

O HO H O O O Me Me NH O Me H Me H O O Me O H HO O H H OH Me

n Rate of Acetal Hydrolysis can be Impacted Considerably

O H O OAr

k1
O OH O

O O

k1 slow

H O H O OAr

k2
JCS Chem. Comm. 1979, 1079

k2 k1

200 n

k2 fast

s*

The exo-Anomeric Effect

n The exo-Anomeric Effect Concerns the Conformation of an O-Glycosidic Linkage (cf. Gauche Effect)

n
O

s* nlp

s*

O O

R H

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

OTMS O O AcOH2C OAc OAc

CH2OAc OTMS AcO O O AcO H

OTMS O H

OAc

AcO OR*

13% nOe

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 t-Bu
N N N Me N N Me
Anderson, J. E.; Roberts, J.D. J. Am. Chem. Soc. 1967, 96, 4186

Me N N Me

t-Bu

N N

t-Bu

t-Bu

t-Bu

G = 0.35 kcal/mol

n Hyperconjugation has Large effects on Even C-H Bonds

IR: "Bohlmann Bands" 2700 to 2800 cm for H4, H6, and H10 Disappear when protonated
Bohlmann, Ber. 1958, 91, 2157 -1 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

H6

H10 N

H4

n Anomeric Effect in Orthoamides can Cause Strange Reactivity:

N N N

N N H N

HBF4 110 C, 1 day

N N

BF4 + H2

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
R S S S S R

G (kcal/mol) 1.64 2.02 2.10 2.46 >2.65 0

SCH3 SPh CO2Me COPh CO2H NMe2

n Carbon is not the only atom through which this effect may be transmitted!
BH2ClMeS
OMe MeH O B Cl

B-Cl bond = 1.890 lit. range: 1.72-1.877

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:
O O P O OH O OEt O P OEt O

2 EtOSPh 78 C r.t.

P(OEt)5

PhSSPh

SPh OEt

2 EtOSPh

N.R.

P O O

P(OEt)5

OH OH

no donation possible

The Role of Hyperconjugation in the Transition State: Theory

n The SN2 Reaction TS looks like a 3c-4e Bond:

CH3Br

I H H

Br

CH3

n MO Diagram for a 3c-4e Bond:

antibonding Basis Set: 2 1 bonding nonbonding

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:
I Entry 1 2 3 4 5 6 7 +
R Cl

Acetone
I R

krel

a-LUMO

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

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

n Data fits the Following Model

I TS HOMO
Cl

p*

Hyperconjugation in Carbonyl Addition Reactions

n The Carbonyl Addition Reaction
Nu
O H H

Nu
Nu

H 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 R RL RM O RM RL H RL RM

Nu

Nu R

OH

Nu

Nu H

OH RM RL

Nu
H R RL RM O H O

Nu
RM R RL H H

Nu
RM O RL H O

Nu
RM H RL

destabilizing interaction

favored

disfavored

destabilizing interaction

predicts wrong product!

disfavored

favored

Ahn and Eisenstein add the Dunitz-Burgi Trajectory and the "Antiperiplanar Effect": Nu
H R RL RM O H O RL

Nu
RM R

destabilizing interaction

rationalized stereochemistry for aldehydes and ketones

favored

disfavored

The "Antiperiplanar Effect":Hyperconjugation in Action

n Polar Substituents act as RL in the Felkin-Ahn Model:
Me Me SMe O Ph

LiBH(s-Bu)3
Me

Me

OH Ph SMe Me

Me

OH Ph SMe

Nu
H R RL RM O

H
H R

i-Pr O
SMe

96:4 syn:anti
Shimagaki Tet. Lett. 1984, 25, 4775

favored

favored

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

nNu
H R RL

s*C-R L
RM O

s*C-R
TS HOMO

Predicts Better Acceptor at RL leads to better selectivity

p*C-O sC-R
OLi

n Sterics Predicts the Opposite Trend:

Me Me

O R Me H

OMe R

OH

O OMe

R= c-C6H11 R= Ph

9:1 syn:anti

>200:1 syn:anti

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
H R 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

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

sTS s*C-H
t-Bu
H H O

s*TS s*C-C
t-Bu
O O

s*TS
O

sTS
disfavored

t-Bu

t-Bu

sC-H
favored

sC-C
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 HO Nu Nu OH

R CO2Me

Nu LAH MeLi NaBH4 MeLi LAH MeLi NaBH4 MeLi

syn:anti
87:13 >90:10 40:60 34:66 35:65 27:73 20:80 17:83

Nu
R R R R R R

CH2OMe CH2=CH2 Et

syn

anti

R=EWG, Shaded bond's s*, better acceptor, F-A predicts anti R=EWG, Shaded bond's, worse donor, Cieplak predicts syn

Chem. Rev. 1999, 99, 1387-1467

n le Noble Has Many Examples with 2-Adamantanones:

R
O

Nu NaBH4 MeLi NaBH4 MeLi NaBH4 MeLi NaBH4 MeLi

syn:anti
57:43 55:45 62:38 70:30 50:50 49:51 48:52 48:52

CO2Me
HO Nu Nu OH

Nu

F TMS SnMe3

syn
Same argument as above

anti

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+ d+ Nu

d-

dEt

CO2Me

CO2Me

Et

is syn product due to simple electrostatic attraction?

is anti product due to 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
O EWG O

EWG H OAc OAc Cl Cl

axial:eq. 60:40 71:29 83:17 71:29 88:12

N.A. A B

EWG

A B

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
O

Axial Approach Trajectory Nu

EWG d -

Nu

favorable

d+
EWG

unfavorable

The b-Silicon Effect: Hyperconjugation Yet Again

n A Silicon b to a Leaving Group Greatly Enhances Ionization
X X

solvent
t-Bu
OTFA

t-Bu

t-Bu

TFAX

kSi kH

TFA = 2.4 x 10
12

bridged intermediates ruled out by Deuterium isotope effects

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

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

TS
Energy

cation
t-Bu

SiR3

sC-Si

sm Rxn Coordinate

hyperconjugation stabilizes cation

n Why is C-Si so much better a donor than C-H? Look at the bonds!
CH CSi Sisp3 BDE 72 kcal/mol

good overlap Csp3

H1s

worse overlap Csp3

BDE 102 kcal/mol

CSi bond has a much higher HOMO

Nucleophillic Olefin Addition Reactions: Homo-Raising Hyperconjugation

n Nucleophillic olefins constitute a key class of reagents
NMe2 H Me O O H Me Me H Me H Me H Me OH Me O Me TMS O H Me

BL2 H

O Me

" O
C H

"

O Me

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

p* s or n 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*

Enamines: A Case Study in Hyperconjugation

n Like amides there is restricted rotation about the C-N bond
Me2N Me2N Me Me2N Me
Relative Energy (kcal/mol)

N,N-Dimethylvinylamine (E)-1-Dimethylaminopropene (Z)-1-Dimethylaminopropene

0 q

+90
Me

Me 0
-90 -60 -30 0 30 60 90

Weston, J.W.; Albrecht, H. J.C.S. Perkin 2, 1997, 1003

"orthoganol in"

Lone Pair Torsion Angle

"orthogonal out"

"gauche in"

"gauche out"

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

Me Me

N
Me

Me

R Me

N
R Me

Me

N
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:
Me

Me2N

2 1
Me

Me2N

Me

N
Me

N
Me

Me

Me
13

1 C NMR: C1: 132.1 ppm C2: 93.4 ppm d = 38.7 ppm

2 H NMR: H1: 5.30 ppm H2: 4.30 ppm d = 1.00 ppm

1

13

gauche out

C NMR: C1: 127.4 ppm C2: 86.3 ppm d = 41.1 ppm

H NMR: H1: 5.76 ppm H2: 4.10 ppm d = 1.66 ppm

orthogonal in

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* More hyperconjugation, higher p HOMO alkene more reactive sC-N Orthogonal In: 2 sC-N to p*: Less hyperconjugation, lower p HOMO alkene less reactive

p*
nN

p*

Mechanism of Enamine Hydrolysis: Implications for Aldol Chemistry

n Two Competing Ideas for Enamine Hydrolysis
Me
+

H
Me N Me

Me H

Me

Me H

O Me

NHMe2

HO

C-protonation
H N

Me

Me

intermol. H transfer
+

Me

Me H

as above

O Me

NHMe2

N-protonation

n Hyperconjugation makes N protonation difficult

Me Me Me N Me MeMe

Me

Me

1:1 AcOH:NaOAc pH=5 5h C-protonation 9:1 d.r.

Me Me Me N N

OAc

80 C equilibration
N

Me

OAc

1:4 d.r.
Me Me Me N

12N HCl or 12N HClO4 rt or 80 C N-protonation

H

stable
Bathlmy, M.; Bessiere, Y. Tetrahedron 1976, 32, 1665

Enamines in the Aldol Reaction: Computational Considerations

n The Enamine Aldol Rection
NMe2 H O Me

H+

Me

Me

O Me

H2O
H

OH Me

n Computed Properties of the Transition State

A surprisingly late transition state: "Normal" Bond Lengths CC CN CO 1.544 1.492 1.470

n What a Late Transition State Means for the Aldol

Me N OMe

Me N OMe

n Protonation only increases product devel in TS 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 H Me H Me O

10 mol% L-Proline DMF, +4 C

H

OH Me Me

80% yield 4:1 anti:syn 99% ee (anti)

n Barbas-List Transition State

n Jorgenson's Transition State

n MacMillan's Transition State

Et

Me

N O H H O O Et

Me

N O H H O O Et

Me

N O H H O O

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 Imporves Hyperconjugation

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

Hyperconjugation Conclusions

It's a simple, but powerful theory.

s*

p*

s*

p*