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*

s p

What is Hyperconjugation?

n A Resonance View:

MeMe

H

H H

H

MeMe

H H

n Frontier Molecular Orbital Depiction:

HH

Me

Me

H

HOMO

LUMOsC-H

p

∆E

Estab

Overlap = S

Estab aS2

∆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

s p

Why is Hyperconjugation Stabilizing?n Remember the H2 Molecule:

n Hyperconjugation Revisited:

HH

Me

Me

H

HOMO

LUMOsC-H

p

∆E

Estab

Overlap = S

Estab aS2

∆E

H1s H1s

H H

distance

Ener

gy

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

Conjugation vs. Hyperconjugation

n Butadiene shows a strong preference for planarity

HHH

H HH

H

HH

∆G = +4 kcal/mol

n Sterics alone cannot account for this large conformational bias

HHH

H

p p*

planar non-planar

planar: non-planar:

p p*no

p

p*

p

p*

Estab aS2

∆E

n Conjugation and Hyperconjugation are essentialy the same phenomenon

orbitals are orthogonal

MO Diagram:MO Diagram:

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

MeMe

H

H H

H

MeMe

H H

"positive hyperconjugation"

MeO2SOMe MeO2S

"negative hyperconjugation"

O

N HMe

Me

O

N HMe

Me

"neutral hyperconjugation"

n Slight, but significant differences in MO diagrams

s p

HH

Me

Me

H

HOMO

LUMO

sC-H

p

n p*

HOMOLUMO

nlp

p*

p

s s*

HOMO

LUMO

nlp-

s*

s

n "Hyperconjugation" will be used to refer to any of the above

OMe

Ranking Electron-Donating Abilityn 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

RRR

> >HR

R

R R >

sp3 carbanion sp2 carbanion p-bond

R

Rsp3-sp3 s-bond

decreasing donating ability

>R

sp3-sp2 s-bond

Csp3 Csp3

sC-C

s*C-CC-C bond: C-F bond:

Csp3

Fsp3

sC-F

s*C-F

Incr

easin

g Do

nor S

treng

th C–C

C–H

C–N

C–O

C–F

n Lone pair energies follow a similar trend

HP

HH

HN

HH

HS

H

HO

HH Cl> > > >

Ranking Electron-Accepting Abilityn 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

Rsp3-sp3 s*

decreasing accepting ability

>R

sp3-sp2 s*

Csp3 Csp3

sC-C

s*C-CC-C bond: C-F bond:

Csp3

Fsp3

sC-F

s*C-F

Incr

easin

g Ac

cept

or S

treng

th

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!

HH

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

n Conformational Preferences of Esters

H

H

HH

H

HH

HH HH

H

Staggered Eclipsed

∆G = +3 kcal/mols s*

HOMO

LUMO

sC-H

s*C-H

sC-H

H

HH

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

HO

Me

Example: MOM-Cl

Cl

H

HO

Me

∆G = +2 kcal/mol

HO

H

Example: H2O2

HO

H

n s*C-Cl

H

O

OMe H

O

OMe

∆G = +4.8 kcal/mol

difference: n s*C-O

H

O

Ot-Bu H

O

Ot-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

Structural Effects of Hyperconjugation: Double Bonds

n IR Stretching Frequencies can Indicate the Degree of Hyperconjugation

NNDH3C

NND

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

OMeO O OMe

>20:1

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

∆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/molAnomeric Effect ≈ 2.8 kcal/mol

O O

X

X

OBz

OBz

BzO

BzOBzOBzO

favored for X=F, Cl, Br, OAc

n Hyperconjugation Explains this Effect:

O O

OMeOMe

n s*no overlap possible

axial anomer: equitorial anomer:

nlp

s*

s

The Anomeric Effect: Consequencesn Spiroketal Conformations are Controled via the Anomeric Effect

OO O O O

O >20:1

n Rate of Acetal Hydrolysis can be Impacted Considerably

HO

O

OH O

O

O

O

OO

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 OArH

H

O O OArH

H

k1

k2

O OOH

k2

k1

≈ 200

JCS Chem. Comm. 1979, 1079

OO

OO

n s*

k1 slow

k2 fast

O

R

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

O

OR

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

HOR*

OTMS

8:1 dr

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:

NN

Nt-Bu

t-Bu

t-Bu NN

Nt-Bu

t-Bu

t-Bu

∆G = –0.35 kcal/mol

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

NN

N

Me

Me Me

MeSolution Structure (NMR):

Anderson, J. E.; Roberts, J.D. J. Am. Chem. Soc. 1967, 96, 4186

N

N

H10H6 H4

IR: "Bohlmann Bands"2700 to 2800 cm-1

for H4, H6, and H10

Disappear when protonated

Bohlmann, Ber. 1958, 91, 2157

1H 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 NN N

NN

Illustrated proton d = 2.3 ppm

HBF4

110 °C, 1 dayN N

N

BF4–

H2+

Erhardt, J.M; Wuest, J.D. J. Am. Chem. Soc. 1980, 102, 6363

The Anomeric Effect: It's not just for Oxygen Anymoren Dithianes Allow the Study of this Effect for Sulfur

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

SS S

S

R

R

R ∆G (kcal/mol)

SCH3SPh

CO2MeCOPhCO2HNMe2

1.642.022.102.46>2.65

≈ 0

OMe

BH2Cl•MeS OBMe

Cl

HB-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 EtOSPhpentane

–78 °CP(OEt)5 + PhSSPh

OP

OO + 2 EtOSPh

r.t. N.R.

P(OEt)5

OH

OHOH O

PO

OOEt

OEt

OP

O O

no donation possible

OEtSPh

The Role of Hyperconjugation in the Transition State: Theory

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

H

H H BrII– 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

Transition State Hyperconjugation Explains Substituent Effects in the SN2 Reaction

n Here's the Rate Data on the SN2 Reaction:

I– + R ClAcetone

I R

Entry R krel a-LUMO

1234567

n-BucylcohexylPhCO2CH2

AllylBenzylNCCH2

PhCOCH2

1.0<0.0001

59.179

1953,070

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

Cl

I–

TS HOMO

p*

p

Hyperconjugation in Carbonyl Addition Reactionsn The Carbonyl Addition Reaction

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

HHO

Nu

p*

OHH

NuNu

HO HH

Felkin Model Predicts Ketones Well, Fails for Aldehydes:

RL

H RMORRL

H RMRO

Nu

destabilizinginteraction

R

O

RL

RMNu

RRL

RM

Nu OH

Nu

favored disfavored

H

O

RL

RMNu

HRL

RM

Nu OH

RL

H RMOH

RL

H RMHO

Nu

destabilizinginteraction

Nu

favoreddisfavored

predicts wrong product!

Ahn and Eisenstein add the Dunitz-Burgi Trajectory and the "Antiperiplanar Effect":

RL

H RMOR

RL

H RMRO

Nu

destabilizinginteraction

Nu

favored disfavored

rationalized stereochemistry for aldehydes and ketones

The "Antiperiplanar Effect":Hyperconjugation in Actionn 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

MeSMe

O

PhLiBH(s-Bu)3

Me

MeSMe

OH

Ph

Me

MeSMe

OH

Ph

96:4 syn:anti

Shimagaki Tet. Lett. 1984, 25, 4775

RL

H RMOR

Nu

favoredSMe

H i-PrOR

favored

H–

RL

H RMOR

nNu

p*C-O

s*C-R L Predicts Better Acceptor at RL leads to better selectivity

n Sterics Predicts the Opposite Trend:

RH

O

Me

Me

Me

OLi

OMeR

OH

Me Me MeOMe

O R= c-C6H11 9:1 syn:antiR= Ph >200:1 syn:anti

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. EvansChem 206 Lecture Notes

s*TS

R

H ROR

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

Os*C-C

sTSt-Bu

O

sC-H

s*TS

Cieplak: Axial Attack Favored

t-Bu

O

sC-C

s*TS

favored disfavored favored disfavored

Transition State Hyperconjugation in C=O Additions: Cieplakn Examples consistent with Cieplak but not Felkin-Ahn

n le Noble Has Many Examples with 2-Adamantanones:

O

RR

Nu

RR

RR

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

LAHMeLi

NaBH4MeLi

LAHMeLi

NaBH4MeLi

87:13>90:10

40:6034:66

35:6527:73

20:8017:83

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

NaBH4MeLi

NaBH4MeLi

NaBH4MeLi

NaBH4MeLi

57:4355:45

62:3870:30

50:5049:51

48:5248:52

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

CO2MeCO2Me

Nu

d

d++

is syn product due to simple electrostatic attraction?

O

EtEt

Nud

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.

AB

AB

H

OAcOAc

ClCl

60:40

71:2983:17

71:2988:12

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 TrajectoryO

EWG

Equitorial Approach Trajectory

d- Nu

unfavorable

favorable

The b-Silicon Effect: Hyperconjugation Yet Againn A Silicon b to a Leaving Group Greatly Enhances Ionization

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

t-Bu

OTFA

Xsolvent

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

Ener

gy

TS

sm

cation

t-Bu

SiR3

hyperconjugationstabilizes 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/molCsp3H1s

BDE ≈ 102 kcal/mol

C–H

good overlap

C–Si

worse overlap

C–Si bond has a much higher HOMO

Nucleophillic Olefin Addition Reactions: Homo-Raising Hyperconjugationn Nucleophillic olefins constitute a key class of reagents

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

HMe

Me

OHO

TMSO

HMe

BL2 O

HMe

NMe2

Me

O

HMe

O

Me

O

HMe

HO

HMe

Me

OMe

OC

" "

H

s or n p*

s or n

p*

p

N.B.: The p orbital is raised in energyMagnitude of HOMO-raising is related to amount of donationto the p*

Enamines: A Case Study in Hyperconjugationn 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

Rela

tive E

nerg

y (

kca

l/m

ol)

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 MeR

NR

Me

Me

NR

Gauche Out

Me

Me

Orthogonal OutOrthogonal In Gauche In

NR

Me

Me

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

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

Me12

13C NMR:C1: 127.4 ppmC2: 86.3 ppm

1H NMR:H1: 5.76 ppmH2: 4.10 ppm∆d = 1.66 ppm∆d = 41.1 ppm

Me

Me

N Me

Me2N Me

1 2

13C NMR:C1: 132.1 ppmC2: 93.4 ppm

1H NMR:H1: 5.30 ppmH2: 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 HOMOalkene more reactive

Less hyperconjugation, lower p HOMOalkene less reactive

Mechanism of Enamine Hydrolysis: Implications for Aldol Chemistryn Two Competing Ideas for Enamine Hydrolysis

NMe Me

H+

H+

NMe Me

NMe Me

H

C-protonation

H

N-protonation

intermol.

H+ transferN

Me Me

H

as above O

Me

NMe Me

HHO

O

Me+ NHMe2

+ NHMe2

n Hyperconjugation makes N protonation difficult

Me Me

N

Me 1:1 AcOH:NaOAc pH=5Me Me

N

Me–OAc 80 °C

Me Me

N

–OAcMe

C-protonationequilibration

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 °CN-protonation

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

Enamines in the Aldol Reaction: Computational Considerationsn The Enamine Aldol Rection

n Computed Properties of the Transition State

NMe2 O

H Me

H+ NMe Me

H2O

H

O

H MeMe

A surprisingly late transition state:

O OH

"Normal" Bond LengthsC–C 1.544 Å

C–N 1.492 Å

C–O 1.470 Å

n What a Late Transition State Means for the Aldol

ONMe

Me

…not this!

ONMe

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"

Proline-Catalyzed Aldol Rection Transition States

n The Direct Aldehyde-Aldehyde Aldol Reaction

H

O

MeH

O

Me

10 mol% L-Proline

DMF, +4 °C

O

HMe

Me

OH 80% yield4:1 anti:syn

99% ee (anti)

n Barbas-List Transition State

H

N

O O

OMe

Et

H

n Jorgenson's Transition State

H

N

O O

OMe

Et

H

n MacMillan's Transition State

H

N

O O

OMe

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 Hyperconjugationn Imporves Hyperconjugation

Hyperconjugation Conclusions

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

It's a simple, but powerful theory.