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Hyperconjugations s*

Alan B. Northrup MacMillan Group Meeting September 17, 2003Review 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 = SH

pMe

HOMO E Estaba

S2 E

H H

Me

LUMO

s

p

sC-HEstab

n Physical Evidence for Hyperconjugation's Existance:

1.431 [SbF5FSbF5] 100.6 1.608

110

1.530

Adamantane

Adamantyl Cation X-Ray StrutureLaube, 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 systemdistance

The FMO View: H H

Energy

H

H H1s H1s

H

H

n Hyperconjugation Revisited:Overlap = SH

pMe

HOMO E Estaba

S2 E

H H

Me

LUMO

s

p

sC-HEstab

Conjugation vs. Hyperconjugationn Butadiene shows a strong preference for planarityH H H H H H H H

G = +4 kcal/molH

planar

non-planar

n Sterics alone cannot account for this large conformational biasplanar:H H H H

non-planar:

orbitals are orthogonal

pMO Diagram:

p*no MO Diagram:

p

p*

p*

p*

p

p

Estab

a

S2 E

n Conjugation and Hyperconjugation are essentialy the same phenomenon

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

LUMO HOMOMe

HOMOH H Me

HOMO

s

p

LUMO

n

p*

s

s*

LUMO

p

p* nlpnlp

s*

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

Ranking Electron-Donating Abilityn 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 donorsC-C bond:

s*C-FCsp3 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 trendH H P H H H S H

sC-F

H

>

>

H

N H

>H

O

>

H

Cl

Ranking Electron-Accepting Abilityn Lower-lying LUMOs are better able to accept electron density> atomic orbitalR R R R R

>

>R

>R

sp p*

sp p* decreasing accepting ability

2

sp3-sp2 s*

sp -sp s*

3

3

n C-X bonds, where X is electronegative lower both s and s* orbitals, making them better acceptorsIncreasing 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-FCsp3 Csp3 Csp3 Fsp3

sC-C n A brief note on overlap:

sC-F

syn =

= good!

anti =

= bad!

Conformational Effects of Hyperconjugation: Single Bondsn Staggered vs. Ecipsed Ethane ConformersHH H H H H HH H H H H

HOMOH H

H H

s*C-H sC-H

H

LUMO

Staggered

Eclipsed

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

s

s*

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

sC-H

n The Gauche EffectExample: MOM-ClCl H O Me H Cl H O Me H

Example: H2O2H O H H H

O

n

s*C-Cl

G = +2 kcal/mol

n Conformational Preferences of EstersO H O Me H O O Me O O O

G = +4.8 kcal/mol

H

t-Bu

H

O

90:10 syn:anti

difference: n

s*C-OBlom, 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 Bondsn IR Stretching Frequencies can Indicate the Degree of HyperconjugationD N H3C N H3C N N D

n

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 HyperconjugationO O O O

s

1715 cm-1

1745 cm-1

1788 cm-1

1813 cm-1

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

>20:1O 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 configurationOMe 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 EffectO Cl O Cl BzO OBz O BzO BzO BzO O X

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

OBz

X

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: Consequencesn Spiroketal Conformations are Controled via the Anomeric EffectO O

O

O O

O

>20:1

n Azaspiracid Stereochemistry at all 5 Anomeric Centers is Predicted by the Anomeric EffectO 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 ConsiderablyO H O OAr

k1O OH O

O O

k1 slow

H O H O OAr

k2JCS Chem. Comm. 1979, 1079

O

k2 k1

O

200 n

k2 fast

H

s*

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

nO

s* nlp

s*

O O

R H

R

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

OTMS O O AcOH2C OAc OAc

O

O

H

CH2OAc OTMS AcO O O AcO H

OTMS O H

OAc

O

O

H

AcO OR*

13% nOe

O

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 Anymoren Similar Effects are Noticed with NitrogenKatritzky, A.R. J.C.S. B 1970, 135

Solution Structure (NMR):t-Bu t-BuN N N Me N N MeAnderson, J. E.; Roberts, J.D. J. Am. Chem. Soc. 1967, 96, 4186

Me N N Me

t-Bu

N N

N

t-Bu

t-Bu

t-Bu

G = 0.35 kcal/mol

n Hyperconjugation has Large effects on Even C-H BondsIR: "Bohlmann Bands" 2700 to 2800 cm for H4, H6, and H10 Disappear when protonatedBohlmann, 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

N

BF4 + H2

Illustrated proton d = 2.3 ppmErhardt, 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 SulfurRR 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!BH2ClMeSOMe MeH O B Cl

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

X-Ray StructureShiner, 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 Reactiviypentane (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.

O

P O O

P(OEt)5

OH OH

no donation possible

The Role of Hyperconjugation in the Transition State: Theoryn 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 Bas