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 H

Me Me

H H

Me Me

n Frontier Molecular Orbital Depiction: Overlap = S H

p

HOMO Me H

Estab

∆E

Me H

s

LUMO

a

S2 ∆E

sC-H

p

Estab

n Physical Evidence for Hyperconjugation's Existance:

1.431 Å [SbF5–F–SbF5]–

110°

Adamantane

1.530 Å

100.6°

1.608 Å

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:

One Central Postulate of FMO Theory

Stabilization of the highest energy electrons stabilizes the entire system

HH

distance

The FMO View:

Energy

H H

H

H H1s

H

H1s

H

n Hyperconjugation Revisited: Overlap = S H

p

HOMO Me H

∆E

Me H

s

LUMO

p

sC-H Estab

Estab

a

S2 ∆E

Conjugation vs. Hyperconjugation n Butadiene shows a strong preference for planarity H

H H

H H

∆G = +4 kcal/mol

H H

planar

H H

non-planar

n Sterics alone cannot account for this large conformational bias planar:

non-planar: H H

H H

p

orbitals are orthogonal

p* no

p

p*

MO Diagram: MO Diagram:

p*

p

p*

p

n Conjugation and Hyperconjugation are essentialy the same phenomenon

Estab

a

S2 ∆E

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

Me Me

O

O

H H H

Me Me

Me

N

Me

H

MeO2S

H

MeO2S

Me

Me

"positive hyperconjugation"

N

OMe

OMe

"negative hyperconjugation"

"neutral hyperconjugation"

n Slight, but significant differences in MO diagrams LUMO

H

HOMO

HOMO

HOMO Me H

Me H

s

p

n

LUMO

s

p*

p

s*

LUMO

s*

p* nlpnlp

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

sp3 carbanion

R

>

R

H

>

R

> R

sp2 carbanion

R

sp3-sp3 s-bond

p-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-F bond:

s*C-C

Increasing Donor Strength

C-C bond:

s*C-F Csp3

Csp3

Csp3 Fsp3

sC-C

sC-F

n Lone pair energies follow a similar trend H H

P H

H

H

>

S H

>

H

N H

H

>

O H

>

H

Cl

C–C C–H C–N C–O C–F

Ranking Electron-Accepting Ability n Lower-lying LUMOs are better able to accept electron density >

R

R

>

R R

>

R

> R

sp p*

atomic orbital

R

sp3-sp2 s*

2

sp p*

3

3

sp -sp s*

decreasing accepting ability

C-C bond:

C-F bond:

s*C-C

s*C-F Csp3

Csp3

Csp3 Fsp3

sC-C

sC-F

Increasing Acceptor Strength

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

n A brief note on overlap:

syn =

= good!

anti =

= bad!

C–F

s*C-F

C–O

s*C-O

C–N

s*C-N

C–C

s*C-C

C–H

s*C-H

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

H

H

HH

H

sC-H

H

LUMO

H

Staggered

s*C-H

H H

H H

H H

H

HOMO

Eclipsed

s

∆G = +3 kcal/mol

s*

H

therefore, each interaction ≈ 1 kcal/mol

sC-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

n The Gauche Effect Example: MOM-Cl Cl H

n

O

Example: H2O2 H

Me H

Cl

s*C-Cl

O

H

Me

O

H

H

O

H

H

∆G = +2 kcal/mol

n Conformational Preferences of Esters O

O H

O

Me

H

O

O O

∆G = +4.8 kcal/mol

H

O

t-Bu

H

Me

difference: n

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

difference: n

s*C-O

O

90:10 syn:anti

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

N

s*

n

D N

N H3C

H3C

s*

N 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

OMe

O 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 O

BzO

O

OBz

Cl

O

BzO BzO

Cl

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

OBz

O X

BzO

X

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 O

HO H

O

H

O

OH O H HO O

Me Me

H

H

NH

Me

O O

O Me

Me

H Me

n Rate of Acetal Hydrolysis can be Impacted Considerably O

H

O

OAr

H

H

O O

H O

O

k1

O

OAr

k2 JCS Chem. Comm. 1979, 1079

OH

O

O

k2 k1

k1 slow

k2 fast

O

≈ 200 n

s*

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

s*

n O

O O

s* nlp

R H

R

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

OTMS

O

O

O

CH2OAc

H

OTMS

AcO

AcOH2C

OAc

O

O

H

O

AcO OR*

O

O

OAc

O

OTMS

AcO

H

H O

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 Solution Structure (NMR):

Katritzky, A.R. J.C.S. B 1970, 135

t-Bu

N

N N

t-Bu

t-Bu

t-Bu

t-Bu

N

Me

N

Me N N

N

t-Bu

N N Me

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

H10

-1

2700 to 2800 cm for H4, H6, and H10

H6

H NMR: Extra Electron Density Causes Shielding

H4

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 N

N

N

N H

HBF4 110 °C, 1 day

N

N

BF4– +

H2

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 S

S

R

S

S

R

∆G (kcal/mol)

SCH3 SPh CO2Me COPh CO2H NMe2

1.64 2.02 2.10 2.46 >2.65 ≈0

n Carbon is not the only atom through which this effect may be transmitted! BH2Cl•MeS MeH

OMe

B-Cl bond = 1.890 Å

O 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 –78 °C

P(OEt)5

+

PhSSPh

SPh OEt

O O P

+

2 EtOSPh

r.t.

N.R.

O OH

P(OEt)5

OH OH

O OEt O P OEt O

O

P O O

no donation possible

The Role of Hyperconjugation in the Transition State: Theory n The SN2 Reaction TS looks like a 3c-4e– Bond:

H

I

–

+

CH3Br

I

I H H

Br

CH3

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: I–

+

R

Acetone

Cl

I

R

Entry

R

krel

a-LUMO

1

n-Bu

1.0

s*C-C

2

cylcohexyl

200:1 syn:anti

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

sC-R

s*TS

R O

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*C-H

O

t-Bu

s*C-C

O

t-Bu

sTS

H H

favored

s*TS

s*TS

O

O

t-Bu

t-Bu

sC-H disfavored

favored

sC-C disfavored

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

Nu

HO

OH

Nu

Nu R

R

R

R

R

R

Nu

syn:anti

CO2Me

LAH MeLi

87:13 >90:10

CH2OMe

NaBH4 MeLi

40:60 34:66

CH2=CH2

LAH MeLi

35:65 27:73

Et

NaBH4 MeLi

20:80 17:83

R

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:

O

HO

Nu

Nu

R

R

syn Same argument as above

Nu

CO2Me

NaBH4 MeLi

57:43 55:45

F

NaBH4 MeLi

62:38 70:30

TMS

NaBH4 MeLi

50:50 49:51

SnMe3

NaBH4 MeLi

48:52 48:52

OH

Nu

R

syn:anti

R

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 Nu

d+ d+

d-

CO2Me

dEt

Et

CO2Me

is anti product due to simple electrostatic repulsion?

is syn product due to simple electrostatic attraction?

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

O

O

EWG EWG

A

B

Diastereomer

EWG

axial:eq.

N.A.

H

60:40

A B

OAc OAc

71:29 83:17

A B

Cl Cl

71:29 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 EWG d -

unfavorable

Nu

favorable

O

d+ 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 OTFA

kSi

TFA–X

TFA =

2.4 x 10

12

kH

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 SiR3

Energy

cation

p

t-Bu

sC-Si

hyperconjugation stabilizes cation

sm Rxn Coordinate

n Why is C-Si so much better a donor than C-H? Look at the bonds! C–Si

C–H

good overlap Csp3

H1s

worse overlap Csp3

Sisp3 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

H

Me

H

Me O

O

OH

O Me

H

H

O

Me

C

Me

H

H

O

"

H

O

Me

Me

" O

BL2

Me

H

Me

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

0° q

N

+90°

8

Me Relative Energy (kcal/mol)

Me2N

6

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

4

2

Me 0 -90

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

"orthoganol in"

-60

-30

0

30

60

Lone Pair Torsion Angle

90

"orthogonal out"

"gauche out"

"gauche in"

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

N

Me

Me

N

R

N

R

R Me

Me

Me

Gauche Out

Orthogonal In

align electron-density on N with p*

Orthogonal Out

Me

N

R Me

Gauche In

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

2 1

N

Me

13

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

Me

gauche out

Me

N

Me 1

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

Me2N

1

Me 13

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

Me

orthogonal in

Me

2 1

H NMR: H1: 5.30 ppm H2: 4.30 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*

More hyperconjugation, higher p HOMO alkene more reactive

p* 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

H Me

N

+

N

Me

Me H

Me

N

Me

O H

HO

+

NHMe2

Me

C-protonation

Me

+

H

H N

Me

intermol.

Me

N

+

H transfer

as above

Me

O

H

+

NHMe2

Me

N-protonation

n Hyperconjugation makes N protonation difficult Me

Me

Me Me

MeMe

1:1 AcOH:NaOAc pH=5

–

5h

N

Me

OAc

N

Me –

80 °C

Me

OAc

N

equilibration

C-protonation 9:1 d.r. Me

Me

1:4 d.r. Me

Me N

Me

12N HCl or 12N HClO4

Me

rt or 80 °C N-protonation

H

X–

N

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

Enamines in the Aldol Reaction: Computational Considerations n The Enamine Aldol Rection NMe2 H

Me

H+

O Me

H

N

Me

O

H2O

O

H

Me

OH 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 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

O

H

H Me

Me

n Barbas-List Transition State

Et

O H

O

O

80% yield Me

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

Me

n Jorgenson's Transition State

Et

H

OH

H

DMF, +4 °C

N

Me

O

10 mol% L-Proline

n MacMillan's Transition State

N

Me

O

Et

H

H

O

O

N

Me

O H

H O

O

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*